Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome

ANTIOXIDANTS & REDOX SIGNALINGVolume 15, Number 7, 2011 FORUM REVIEW ARTICLE ª Mary Ann Liebert, Inc.
DOI: 10.1089/ars.2010.3739 Oxidative Stress as Pathogenesis of Cardiovascular Risk Associated with Metabolic Syndrome Metabolic syndrome (MetS) is characterized by accumulation of visceral fat associated with the clustering ofmetabolic and pathophysiological cardiovascular risk factors: impaired glucose tolerance, dyslipidemia, andhypertension. Although the definition of MetS is different among countries, visceral obesity is an indispensablecomponent of MetS. A growing body of evidence suggests that increased oxidative stress to adipocytes is centralto the pathogenesis of cardiovascular disease in MetS. Increased oxidative stress to adipocytes causes dysre-gulated expression of inflammation-related adipocytokines in MetS, which contributes to obesity-associatedvasculopathy and cardiovascular risk primarily through endothelial dysfunction. The purpose of present reviewis to unravel the mechanistic link between oxidative stress and cardiovascular risk in MetS, focusing on insulinresistance, hypertension, and atherosclerosis. Then, therapeutic opportunities translated from the bench tobedside will be provided to develop novel strategies to cardiovascular risk factors in MetS. Antioxid. RedoxSignal. 15, 1911–1926.
inflammatory state, which contributes to obesity-associatedvasculopathy and cardiovascular risk (12, 76, 87). These Metabolic syndrome (MetS) is characterized by accu- adipocytokines are generally divided into pro-inflammatory mulation of visceral fat associated with the clustering of cytokines such as tumor necrosis factor-a, interleukin-6, metabolic and pathophysiological cardiovascular risk factors: monocyte chemoattractant protein-1, plasminogen activator impaired glucose tolerance (IGT), dyslipidemia, and hyper- inhibitor-1, and anti-inflammatory cytokines such as adipo- tension (HTN) (47). Although the definition of MetS is dif- nectin. Imbalance between pro-inflammatory cytokines and ferent among countries, visceral obesity is an indispensable anti-inflammatory cytokines is responsible for oxidative stress component of MetS. The prevalence of MetS is rapidly in- especially to endothelial cells and underlies the pathogene- creasing worldwide not only in industrialized countries but sis of the obesity-associated insulin resistance, IGT, type-2 also in developing countries associated with an increase in diabetes mellitus (T2DM), HTN, dyslipidemia, and vascular food intake. MetS has a strong impact on the global incidence disease. Although obstructive sleep apnea syndrome repre- of the life-threatening cardiovascular disease such as stroke sents another important cause of oxidative stress in MetS and myocardial infarction (2, 53). Although the MetS is mul- (67, 77), this topic will not be discussed in this review be- tifactorial in origin, IGT, dyslipidemia, and HTN are caused cause unlike the increase in visceral adipose tissue, which by the same underlying mechanism—endothelial dysfunction is involved in a definition of MetS, not all the individuals primarily mediated by oxidative stress.
with MetS are associated with obstructive sleep apnea It is now apparent that visceral adipose tissue is an endo- crine organ that secretes many bioactive molecules, known The purpose of the present review is to overview the as adipocytokines (20, 134, 152). The production of adipocy- mechanistic link between oxidative stress and cardiovascular tokines is of particular interest, because their local secretion risk in MetS based on the evidence obtained from animal by perivascular adipose depots may provide a new mecha- experiments and clinical trials. This review specifically fo- nistic link between obesity and its associated cardiovascu- cusses on insulin resistance and atherosclerosis, which are lar complications. Increased oxidative stress to adipocytes intimately related to oxidative stress to endothelial cells. Then, causes dysregulated expression of inflammation-related therapeutic opportunities translated from the bench to bed- adipocytokines in MetS. Increasing evidence supports the side will be provided to develop novel strategies for pre- central role of adipose tissue in the development of systemic venting cardiovascular risk associated with MetS.
Second Department of Internal Medicine, Kansai Medical University, Moriguchi City, Japan.

Mechanisms Underlying Cardiovascular Risk in MetS Central role of oxidative stressin visceral adipose tissue A growing body of evidence suggests that increased oxi- dative stress in white adipose tissue is central to the patho-genesis of cardiovascular disease in MetS. Although themolecular mechanism of oxidative stress to adipocytes re-mains unclear and appears to be multifactorial, the develop-ment of adipocyte hypertrophy and hypoxia has beenimplicated in oxidative stress (54). Reactive oxygen species(ROS) production increases in parallel with fat accumulationin adipocytes and increased levels of fatty acid stimulate ROSproduction in adipocytes through the activation of NADPHoxidase and decreased expression of antioxidative enzymes(49). Exposure of adipocytes to oxidative stress decreasesanti-inflammatory adiponectin (57, 133) and increases pro-inflammatory adipocytokines (23, 49, 121). Involvement of alocal renin-angiotensin aldosterone system (RAAS) has alsobeen proposed as a potential mediator of oxidative stress toadipocytes (22). Irrespective of the mechanism of ROS pro-duction, oxidative stress in the visceral adipose tissue is anupstream event that mediates systemic inflammation and Mechanism of obesity-induced cardiovascular oxidative stress in the remote tissue through dysregulation of risk. In white adipose tissue (WAT) reactive oxygen species adipocytokine production. Systemic inflammation then cau- (ROS) production increases in parallel with fat accumulation ses a variety of metabolic and cardiovascular disorders in adipocytes through the activation of NADPH oxidase and through oxidative stress to endothelial cells (Fig. 1).
decreased expression of antioxidative enzymes. Oxidativestress in WAT causes dysregulation of adipocytokines; in-creased generation of pro-inflammatory cytokines such as Oxidative stress and insulin resistance plasminogen activator inhibitor (PAI)-1, tumor necrosis fac-tor-a (TNF-a), and monocyte chemoattractant protein-1 Oxidative stress to endothelial cells and subsequent de- (MCP-1); and decreased generation of anti-inflammatory crease in glucose uptake and utilization by major energy- cytokines such as adiponectin. Dysregulation of adipocyto- consuming organs such as the liver and skeletal muscle are kines causes oxidative stress to remote tissues and systemic responsible for insulin resistance. In MetS, endothelial cells inflammation responsible for endothelial cell dysfunction, are directly exposed to ROS through high levels of circulating which is central to the pathogenesis of insulin resistance, pro-inflammatory cytokines generated in the visceral adipose diabetes, and atherosclerosis in metabolic syndrome (MetS).
tissue and low levels of adiponectin. Moreover, endothelial This illustration is adapted from Furukawa et al. (49).
cell generation of ROS is increased by activation of NADPHoxidase through the action of local RAAS (31, 73). Indeed,RAAS-associated signaling by way of the angiotensin (Ang) II metabolically active tissues contributing to the impairment of type-1 receptors and mineral corticoid receptors triggers tis- insulin-stimulated glucose and lipid metabolism.
sue activation of the NADPH oxidase and increased produc- Another critical effect of ROS on the glucose uptake tion of ROS in endothelial cells (132). This vicious cycle of ROS mechanism is the activation of serine/threonine kinase generation in endothelial cells is an important mechanism of cascades such as c-Jun N-terminal kinase and nuclear factor- transition from insulin resistance and IGT to T2DM in MetS.
kappaB, and others that in turn phosphorylate multiple Oxidative stress to endothelial cells decreases bioavail- targets, including the insulin receptor and the insulin receptor ability of nitric oxide (NO) and causes loss of blood flow substrate (IRS) proteins (14, 43, 104). Increased serine phos- regulation in response to increased oxygen demand and en- phorylation of IRS reduces its ability to undergo tyrosine ergy utilization. Reduced bioavailability of NO results from phosphorylation and may accelerate the degradation of IRS-1 decreased synthesis by uncoupling of endothelial NO syn- (7), leading to the disruption of signaling pathways for glu- thase (eNOS) through ROS-induced oxidation and depletion cose uptake by glucose transporter-4 (GLUT4) through IRS-1 of the eNOS cofactor, tetrahydrobiopterin (BH4) (11, 125), in and phosphatidylinositol 3-kinase (PI3K)/Akt. GLUT4 causes combination with enhanced consumption in tissues by high impairment of insulin-stimulated skeletal muscle glycogen levels of superoxide generating peroxynitrite. This molecule is synthesis, which appears to underlie the mechanism of insulin highly toxic and causes endothelial cell death (36) that further resistance (19).
reduces endothelial cell generation of NO. eNOS-derived NO Impaired glucose uptake by adipocytes thorough the IRS-1, also plays a crucial role in angiogenesis by upregulating PI3K/Akt, and GLUT4 axis may cause an additional adverse vascular endothelial growth factors and increasing mobiliza- effect on insulin resistance. Adipose tissue has been proposed tion of endothelial progenitor cells from the bone marrow (41, to act as a glucose sensor (138). Adipocytes, therefore, detect 82). Thus, ROS-induced endothelial dysfunction impairs the absence of glucose uptake by GLUT4 and, in response, blood flow regulation and reduces expansion of the capillary secrete adipocytokines such as retinol-binding protein 4 to network, with attenuation of microcirculatory blood flow in restrict glucose uptake in the skeletal muscle and increase

OXIDATIVE STRESS AND METABOLIC SYNDROME glucose output by the liver by blocking insulin signaling (95), models of HTN, a unifying characteristic of these models is thereby increasing the blood glucose level. It was found that the presence of oxidative stress that participates in the main- the expression of GLUT4 is reduced in adipocytes, but not in tenance of elevated arterial pressure and seems to be a com- skeletal muscle, of animals and humans with obesity and mon denominator underlying endothelial dysfunction in T2DM (127). Thus, oxidative stress-induced downregulation various forms of experimental HTN. In the presence of oxi- of GLUT4 in adipocytes is a representative mechanism of in- dative stress, eNOS acts as a double-edged sword. Superoxide sulin resistance and T2DM in MetS. The putative model of produced by inflammatory cells or endothelial cells stimu- insulin resistance and T2DM in MetS is illustrated in Figure 2.
lated with pro-inflammatory adipocytokines react with NO,thereby stimulating the production of peroxynitrite. Perox- Oxidative stress and HTN ynitrite in turn causes uncoupling of eNOS, thereforeswitching an antiatherosclerotic NO-producing enzyme to Endothelial dysfunction contributes to HTN, one of the an enzyme that may accelerate the atherosclerotic process diagnostic criteria of MetS. Reduced bioavailability of NO by producing superoxide (69, 94). Besides circulating in- appears to be a key process through which endothelial dys- flammatory cells and pro-inflammatory adipocytokines, there function is manifested in HTN. Accumulating evidence sug- are a variety of sources of ROS in the vascular tissue. ROS- gests that NO plays a major role in regulating blood pressure producing enzymes involved in increased oxidative stress and that impaired NO bioactivity is an important mechanism within the vascular tissue include NADPH oxidase, xanthine of HTN (78, 125, 141, 145). Mice with disruption of the gene oxidase, and mitochondrial superoxide-producing enzymes.
for eNOS have elevated blood pressure levels compared with Of these, local RAAS-mediated NADPH oxidase activation is control animals (128, 135), suggesting a genetic component to of prime importance in endothelial cell generation of ROS, the link between impaired NO bioactivity and HTN. Al- which contributes to endothelial dysfunction and HTN (122).
though the contribution of NO may vary between different Oxidative stress-induced uncoupling of NOS is not con- fined to eNOS. Oxidative stress on endothelial cells increasesexpression of inducible NOS (iNOS). Unlike eNOS, iNOS isconstitutively active and generates robust NO. Because oxi-dative stress depletes BH4 and uncouples iNOS, it is possiblethat iNOS uncoupling exaggerates oxidative stress and cre-ates a vicious cycle of endothelial dysfunction and HTN.
The potential role of NOS uncoupling in HTN and the ther-apeutic opportunity that targets NOS uncoupling will bediscussed later.
Oxidative stress and atherosclerosis Atherosclerosis is one of the representative manifestations of vascular pathology in MetS. Development of insulin resis-tance, HTN, and dyslipidemia culminates in atherosclerosis.
A growing body of evidence indicates that pro-inflammatorycytokines generated in the visceral adipose tissues are associ-ated with atherosclerosis. A sequence of events that are par-ticipated in the development of atheromatous plaque isillustrated in Figure 3.
One of the triggers of atheromatous plaque formation is endothelial generation of ROS (Fig. 3A). Another initial par- Schematic drawing of the role of oxidative stress ticipant in atheromatous lesion-prone sites includes the inti- to adipocytes in insulin resistance. Oxidative stress to adi- mal influx and accumulation of low-density lipoprotein pocytes causes dysregulation of adipocytokines that mediate (LDL), which is further enhanced in the presence of triglyc- systemic inflammation and oxidative stress to endothelial eride. LDL is oxidized by ROS, and oxidized LDL is taken up cells (ETCs) and major energy-consuming organs such as by macrophages via their scavenger receptors CD36 to form liver and skeletal muscles. Oxidative stress to ETCs promotes foam cells (26, 115, 143). Monocyte-macrophage recruitment uncoupling of endothelial nitric oxide synthase (eNOS) andreduces bioavailability of NO that impairs blood flow in to the intima is likely to be regulated not only by a multiplicity metabolically active tissues, leading to the impairment of of adhesion molecules, integrins, and selectins, but also by insulin-stimulated glucose utilization. Oxidative stress to chemokines such as monocyte chemoattractant protein-1, major energy-consuming organs, on the other hand, in- which is constitutively synthesized and secreted by endo- creases serine phosphorylation and degradation of insulin thelial cells and smooth muscle cells (SMCs) migrated from receptor substrate (IRS) and disrupts signaling pathways for the media and adventitia (16, 153). Transcriptional upregu- glucose uptake by glucose transporter-4 (GLUT4) through lation of these molecules is enhanced by ROS, which are de- the IRS-1 and phosphatidylinositol 3-kinase/Akt signaling rived from endothelial cells, activated macrophages, and pathway. Impaired glucose uptake by adipocytes thorough SMCs. On the other hand, such ROS are also pivotal in the GLUT4 causes secretion of retinol-binding protein 4 (RBP4) oxidation of LDL, creating a self-perpetuating cycle in foam to restrict glucose uptake in skeletal muscle and increaseglucose output by the liver, thereby reducing glucose utili- cell accumulation and atherosclerotic plaque formation. At zation and contributing to insulin resistance.
the same time, SMCs migrate from the media to the intimal

events participated in thedevelopment tous plaque. (A) An earlyphase of atheromatous plaqueformation.
cytokines trigger endothelialcell (ETC) generation of ROSby activating NADPH oxidase(NOX) and xanthine oxidase(XO). These ROS promoteeNOS uncoupling and accen-tuate ROS generation. The in-timal influx and accumulationof (LDL) represents another trig-ger of atheromatous plaqueformation. LDL is oxidizedby ROS, and oxidized LDL(OxLDL) is taken up by mac-rophages via their scavengerreceptors CD36 to form foamcells. ROS stimulate mono-cyte-macrophage recruitmentto the intima by enhanced ex-pression of adhesion mole-cules and chemokines. At thesame time smooth muscle cells(SMCs) migrate from the me-dia to the intimal endotheliallayer, differentiated into myo-fibroblasts (MFs), and prolif-erate under the regulation of anumber of mitogens, includ-ing platelet-derived growthfactor (PDGF) and insulin.
Proliferating MFs synthesizecollagen and promote thick-ening of the intima. (B) Alate stage of atheromatous pla-que development. A robust in-crease in inflammation andoxidative stress causes apopto-sis of foam cells, leading to theformation of the necrotic lipidcore. The necrotic lipid core iscovered with a thin fibrous cupcreating unstable plaque as aresult of degradation of colla-gen fiber by metalloproteinases(MMPs) in the presence of ROS.
endothelial layer. They are differentiated into myofibroblasts trix metalloproteinases in the presence of ROS (79, 151). The and proliferate under the regulation of a number of mitogens, thin fibrous cup is prone to be ruptured in response to in- including platelet-derived growth factor (37, 97). Insulin also creased shear stress caused by elevated intraluminal pressure acts as a growth factor and enhances intimal myofibroblast and luminal narrowing of the coronary artery (92, 157).
growth when serine residues of IRS-1 are phosphorylated by Therefore, such an advanced atheromatous plaque consisted oxidative stress (65, 149). In addition, collagen synthesis by of necrotic lipid core covered with a thin fibrous cap is termed proliferating myofibroblasts is substantial for the thickening unstable plaque.
of the intima.
In the late stage of plaque development (Fig. 3B), a robust increase in inflammation and oxidative stress causes apo- for Cardiovascular Risk Factors in MetS ptosis of foam cells and is responsible for the formation of thenecrotic lipid core (64, 84). The necrotic lipid core is covered Therapeutic approaches to MetS comprises lifestyle modi- with a fibrous cup enriched with collagen fiber. However, the fication in conjunction with drug treatment of the MetS- fibrous cap is degraded by redox-sensitive activation of ma- associated complications. Healthier eating and regular OXIDATIVE STRESS AND METABOLIC SYNDROME exercise greatly reduce waistline and body mass index, lower described before. Although many model organisms have blood pressure, and improve lipid profile. Lifestyle modifi- consistently demonstrated positive responses to CR, it re- cation has been shown to prevent T2DM development.
mains to be shown whether CR will extend lifespan in hu- Nevertheless, appropriate treatment of cardiovascular risk mans. The first results from a long-term, randomized, factors in MetS often requires pharmacologic intervention controlled CR study in nonhuman primates showing statis- against IGT or T2DM with insulin-sensitizing agents, such as tically significant benefits on longevity have now been re- thiazolidinediones (TDZs) and metformin, whereas statins ported (27). Additionally, positive results from short-term, and fibrates or angiotensin-converting enzyme (ACE) in- randomized, controlled CR studies in humans are suggestive hibitors and Ang II type-1 receptor blockers (ARBs) are the of potential health and longevity gains (61). However, the first-line lipid-modifying or anti-HTN drugs. These pharma- current environment of excess caloric consumption and high cological interventions inhibit oxidative stress, but unlike incidence of overweight/obesity illustrate the improbable general antioxidants of which efficacy to prevent cardiovas- nature of the long-term adoption of a CR lifestyle by a sig- cular risk factors is still controversial, they prevent only nificant proportion of the human population. Thus, the search harmful ROS generation, leaving beneficial ROS. Thus, these for substances that can reproduce the beneficial physiologic drugs are designated as a class of preventive antioxidants en- responses of CR without a requisite calorie intake reduction, abling a causal therapy against oxidative stress through site- termed CR mimetics, has gained momentum.
specific inhibition of ROS and preservation of redox signaling The molecular mechanism underlying the efficacy of re- necessary for cardiovascular protection (107). Further, pre- duction of visceral fat mass by CR to reduce cardiovascular ventive antioxidants appear to increase eNOS-derived NO, risk factors may be related to increased generation of adipo- which prevents insulin resistance, HTN, and atherosclerosis nectin in the visceral adipocytes (158). It has been demon- (98). Discussed in this section are therapeutic opportunities for strated that CR in rats significantly increases the level of cardiovascular risk factors in MetS focusing on the strategy to circulating adiponectin, a distinctive marker of differentiated inhibit oxidative stress and inflammation in the visceral adi- adipocytes (167). PPAR-c is a member in the nuclear receptor pose tissue and preserve endothelial functions NO generation superfamily that mediates part of the regulatory effects of that are central to prevent cardiovascular risk factors in MetS.
dietary fatty acids on gene expression and may be a molecularlink between CR and increased generation of adiponectin. CRfor 2 and 25 months, significantly increased the expression of Caloric restriction and adiponectin PPAR-c, C/EBPb, and Cdk-4, and partially attenuated age- A large body of experimental and epidemiological evi- related decline in C/EBPa expression relative to rats fed ad dence has established an association between visceral obesity libitum (166). As a result, adiponectin was upregulated at both and MetS. Caloric restriction (CR) primary affects energy mRNA and protein levels, resulting in activation of target stores in visceral adipose tissue (32). Indeed, a substantial genes involved in fatty acid oxidation and fatty acid synthesis.
improvement in all aspects of MetS with only a moderate Moreover, CR significantly decreased the ratio of C/EBPb degree of weight loss by CR has been observed in a large isoforms LAP/LIP, suggesting the suppression of gene tran- number of randomized, controlled studies and can also be scription associated with terminal differentiation while facil- obtained in severe obesity, despite the fact that the patients itating preadipocytes proliferation. Morphometric analysis remain obese (33). The reasons for this apparent dissociation revealed a greater number of small adipocytes in CR relative between weight loss and metabolic improvement are not yet to ad libitum feeding. Immunostaining confirmed that small clearly understood, but may involve the relationship between adipocytes were more strongly positive for adiponectin than visceral fat and metabolic alterations. The results of some the large ones. Overall, these results suggest that CR increased studies suggest that the favorable metabolic changes observed the expression of adipogenic factors and maintained the dif- in obese patients with CR and weight loss may be directly ferentiated state of adipocytes, which is critically important attributable to a reduction in visceral fat (59). Moreover, vis- for adiponectin biosynthesis. On the other hand, adiponectin ceral adipose tissue is a pivotal organ in aging process and in is a CR mimetic. It has been demonstrated that mice with the determination of life span. There is growing evidence that transgenic expression of human adiponectin that had persis- the effect of reduced adipose tissue mass on life span could be tent hyperadiponectinemia exhibited significantly decreased due to the prevention of obesity-related metabolic disorders, weight gain associated with less fat accumulation and smaller including T2DM and atherosclerosis (15).
adipocytes in both visceral and subcutaneous adipose tis- The mechanism underlying improvements of the aspect of sues (106). Macrophage infiltration in adipose tissue was MetS and prevention of aging by CR has been extensively markedly suppressed in the transgenic mice. In the hyper- investigated. Aging is associated with increased visceral fat, adiponectinemic mice, daily food intake was not altered, but and recent studies suggested that visceral fat could influence oxygen consumption was significantly greater, suggesting longevity (88, 96, 163). It has recently been proposed that si- increased energy expenditure. Moreover, high-calorie diet– lent information regulator 2 (SIR2) ortholog, sirtuin 1 (SIRT1), induced premature death was almost completely prevented the mammalian ortholog of the life-extending yeast gene SIR2 in the hyperadiponectinemic mice in association with atten- are involved in the molecular mechanisms linking lifespan to uated oxidative DNA damage. The transgenic mice also adipose tissue. SIRT1 represses peroxisome proliferator-acti- showed longer life span on a conventional low-fat chow.
vated receptor (PPAR)-c transactivation and inhibits lipid Adiponectin circulates mainly as a low-molecular-weight accumulation in adipocytes (113). The favorable effect of ad- (180 kDa) hexamer and a high-molecular-weight (*360 kDa) ipose tissue reduction on lifespan could be due to increased multimer. Adiponectin multimers exert differential biologic production of anti-inflammatory adipocytokines and de- effects, with the high-molecular-weight multimer associ- creased production of pro-inflammatory adipocytokines as ated with favorable metabolic effects, that is, greater insulin

sensitivity, reduced visceral adipose mass, reduced plasma clearance of apoptotic cells in advanced plaques (144). Mole- triglycerides, and increased high-density lipoprotein (HDL)- cular structure of adiponectin is akin to complement C1q, and cholesterol (75), and adiponectin knockout mice manifest in- adiponectin binds to a number of target molecules, including sulin resistance, IGT, and dyslipidemia (168). Adiponectin, damaged endothelium and the surface of apoptotic cells (110).
thus, influences atherosclerosis by affecting the balance of Thus, adiponectin may play a crucial role in efferocytosis and atherogenic and antiatherogenic lipoproteins in plasma, and prevention of vulnerable plaque formation. Although a recent by modulating cellular processes involved in foam cell for- study showed lack of association between adiponectin levels mation. The metabolic effects of adiponectin are mediated and atherosclerosis (99), this attractive hypothesis needs to be thorough adiponectin receptor-1 and adiponectin receptor-2 explored. The potential roles of adiponectin in prevention of (68). These adiponectin receptors are linked to AMP-activated cardiovascular risk are illustrated in Figure 4.
protein kinase (AMPK) and PPAR-a, respectively. AMPK is acellular energy sensor that contributes to the regulation of energy balance and caloric intake (21, 150). The activity of Several nonpharmacological interventions can prevent AMPK is determined by cellular AMP/ATP. AMPK can endothelial dysfunction or improve impaired endothelium- phophorylate several enzymes involved in anabolism to dependent vasodilation. Probably, the most effective non- prevent further ATP consumption, and induces some cata- pharmacological measure for the management of MetS is bolic enzymes to increase ATP generation. Further, AMPK represented by aerobic physical activity, which can reduce stimulates glucose utilization in the skeletal muscle and in- production of oxidative stress associated with increasing age.
hibits gluconeogenesis in the liver (159). On the other hand, It has been demonstrated that exercise alone is an effective PPAR-a participates in fatty acid oxidation, thereby increas- nonpharmacological treatment strategy for insulin resistance, ing energy consumption.
MetS, and cardiovascular disease risk factors in older obese Adiponectin is known to enhance ischemic tolerance in the adults (160). In addition, several randomized, controlled heart. It has been demonstrated that short-term CR increases studies have shown that aerobic types of exercise are protec- adiponectin levels and exerts a cardioprotective effect againstischemia/reperfusion injury in the wild-type mouse but notadiponectin antisense transgenic mouse heart (131), suggest-ing that adiponectin is an obligatory mediator of CR-inducedischemic tolerance in the heart. This cardioprotective effect ofadiponectin is mediated by AMPK-mediated signaling. Pro-longed CR also confers ischemic tolerance, but this effect isindependent of AMPK and mediated by a NO-dependentincrease in nuclear Sirt1 (130), which is responsible for a NAD-dependent deacetylase and prevention of apoptosis in cardiacmyocytes (3). Thus, CR increases ischemic tolerance viaadiponectin- and Sirt1-dependent mechanisms.
Cardioprotection by adiponectin is at least in part mediated by an antioxidative/nitrosative effect. The recent study hasdemonstrated that adiponectin reduces oxidative/nitrosativestress by inhibiting NADPH oxidase and iNOS expressionand ameliorates ischemia/reperfusion injury in mice (139),and this action is AMPK independent (154). A recent study(86) using a rat model of nonalcoholic steatohepatitis suggeststhat this antioxidative effect may be mediated by adiponectinreceptor-2.
Potential roles of adiponectin in the prevention of Adiponectin also acts as an anti-inflammatory molecule cardiovascular risk factors. Small adipocytes in the visceral through a receptor-independent mechanism. The serum adipose tissue in nonobese subjects increase generation of adi-ponectin through adiponectin receptor-1 (AdipoR1) and adi- concentration of adiponectin exceeds a micromolar level that ponectin receptor-2 (AdipoR2)-dependent and -independent is extremely higher than estimated its receptor density. Thus, mechanisms. AdipoR1 improves insulin resistance and inhibits receptor-independent mechanism has been implicated in the development of type-2 diabetes mellitus (T2DM) by in- the anti-inflammatory action of adiponectin. This anti- hibiting gluconeogenesis in the liver and stimulating glucose inflammatory effect may play a crucial role in preventing utilization in the skeletal muscle through the action of AMP- the development of atherosclerosis and vulnerable plaque.
kinase (AMPK). The AdipoR1-AMPK signaling also confers Plaque necrosis arises from a combination of foam cell apo- tolerance to ischemia/reperfusion (I/R) injury. AdipoR2 in- ptosis and defective clearance of these dead cells, a process creases free fatty acid (FFA) oxidation and energy consumption called efferocytosis (137). Defective efferocytosis contributes though the activation of peroxisome proliferator activated re- to necrotic core and the vulnerable plaque formation within ceptor-a (PPAR-a), thereby preventing T2DM and dyslipide-mia. AdipoR2 may also be involved in tolerance to I/R injury advanced atheroma that is thought to promote plaque dis- by inhibiting oxidative/nitrosative (O/N) stress (dotted line). A ruption and, ultimately, acute atherothrombotic vascular receptor-independent action of adiponectin (AN) is involved in disease (144). Molecular-genetic causation studies in mouse an antiatherosclerotic effect through dead cell clearance and models of advanced atherosclerosis have provided evidence inhibition of inflammation by acting as a complement for that several molecules known to be involved in efferocytosis, macrophages to eliminate apoptotic cells from the atheroma- including complement C1q, play important roles in the tous plaque.

OXIDATIVE STRESS AND METABOLIC SYNDROME adiponectin levels (6, 83, 101). Conversely, exercise trainingmay influence pro-inflammatory cytokine production (18, 46,148). Future studies are needed to investigate the cellularmechanisms by which exercise training affects inflamma-tion and whether alterations in inflammation are one mecha-nism by which exercise improves components of MetS inat-risk individuals.
Antagonists against RAAS Any anti-HTN therapies have been shown to reduce the risk of total major cardiovascular events. Recently, the rele-vance of the type of anti-HTN therapy used to treat HTNpatients in facilitating the development of T2DM has beendemonstrated in different trials. The recognition of the riskpresent in HTN patients with MetS for developing T2DMreinforces the need to consider the ideal anti-HTN therapy,either mono or combination, in these patients. The available Schematic drawing of therapeutic opportunities evidence showing that an ACE inhibitor or an ARB is the most for prevention of cardiovascular disease in MetS. MetS is suitable therapy to be started in these patients, alone or in characterized by the cluster of cardiovascular risk factors: combination, due to their capacity to prevent or retard the impaired glucose tolerance (IGT), hypertension (HTN), and development of T2DM (48, 124).
dyslipidemia that culminate in cardiovascular disease. Re-duction of visceral fat by caloric restriction (CR) and exercise Adipocytes are a suggested source of components of the increases adiponectin and decreases inflammatory cytokines, RAAS, with regulation of their production related to obesity- thereby inhibiting systemic inflammation and oxidative HTN (22). Ang II has been demonstrated to promote oxidative stress (OS) to endothelial cells (ETCs). Inhibition of the renin- stress via overexpression of NADPH oxidase in adypocytes angiotensin-aldosterone system (RAAS) by employing an (50, 66). It has been demonstrated that blockade of Ang II angiotensin converting inhibitor (ACEI) or angiotensin II type-1 receptors reduces oxidative stress in adipose tissue and type-1 receptor blocker (ARB) is more direct approach to ameliorates adipocytokine dysregulation (74). Therefore, inhibit OS to ETCs. Antidyslipidemic agents, statin and ei- ACE inhibitors and ARBs represent promising tools for in- cosapentaenoic acid (EPA), exert ETC protection indepen- hibiting oxidative stress in adipocytes, thereby preventing the dent of their effects on LDL and triglyceride (TG) levels.
production of pro-inflammatory adipokines responsible for Fibrates, on the other hand, decrease TG and increase high-density lipoprotein (HDL), thereby preventing atherosclero- systemic inflammation and oxidative stress in MetS.
sis. Although OS to ETCs promotes further generation ofROS that inhibit bioavailability of NO by generating perox- Insulin sensitizers ynitrite or causing uncoupling of NO synthase, ETC-derived There are a number of pharmacological tools for treatment NO synthesis can be increased by resveratrol and an NO of T2DM. Ever since insulin was discovered in the early 20th synthase cofactor tetrahydrobiopterin (BH4). Antidiabeticagents such as metformin and thiazolidinediones (TDZs) that century, it had been an only drug in patients with insulin- act through an increase in insulin sensitivity improve not dependent DM and T2DM for many years. Then, sulfonyl only IGT but also hyperinsulinemia responsible for athero- urea became available in the mid 20th century, and it had been sclerosis and cardiovascular disease.
a first choice of drugs in patients with T2DM. However, rec-ognition of deleterious cardiovascular effects of hyper- tive against age-related increases in visceral adiposity in insulinemia in patients with T2DM has shifted paradigm of growing children and adolescents (72). Moreover, physical T2DM treatment from increasing blood insulin level to insulin activity can improve endothelial dysfunction even in patients sensitivity. Insulin acts as not only blood glucose-lowering with cardiovascular risk factors such as essential HTN. It is hormone but also acts as a growth factor under oxidative worth noting that most of nonpharmacological measures for stress that may be involved in atherosclerosis. Ruige and as- prevention of cardiovascular risk act by preventing or reducing sociates (119) have demonstrated that hyperinsulinemia is an inflammation and oxidative stress. Current evidence supports independent risk factor of coronary artery disease. In addi- that aerobic exercise, alone or combined with CR, improves tion, insulin activates the PI3K-Akt axis that is known to symptoms of MetS, possibly by altering systemic levels of in- play a role in the control of aging (9, 109), thereby possibly flammatory adipocytokines (162). A number of studies show restricting life span. On the contrary, pharmacological inter- that increased physical activity leads to lower circulating levels ventions that increase insulin sensitivity reduce cardiovas- of pro-inflammatory cytokines and higher levels of adipo- cular complications and are, therefore, expected to promote nectin. The mechanism underlying reduced oxidative stress in longevity. A PPAR-c activator TZD and metformin are quite visceral white adipose tissue by exercise may be related to the promising tools to substantially improve the cluster of car- decreased expression of NADPH oxidase in addition to an diovascular risk factors in patients with MetS complicated enhanced antioxidant defense system, and the prevention of with T2DM, whereas a-glucosidase inhibitors may also dysregulated production of inflammation-related adipocyto- be effective to prevent hyperinsulinemia by inhibiting kines (121), suggesting that exercise is a fundamental approach postprandial hyperglycemia. A newly emerged antidiabetic to protect against cardiovascular risk in MetS. However, lim- drug dipeptidyl peptidase-IV (DPP-4) inhibitors increase ited data show that exercise training does not influence serum glucose-dependent stimulation of insulin secretion, and unlike sulfonyl urea it do not cause hypoglycemia or inhibit ATP- metformin improves endothelial functions in Otsuka Long- sensitive potassium channels that are thought to be crucial in Evans Tokushima fatty rat mesenteric arteries by suppressing cytoprotection in both pancreatic islet b-cells and cardiomyo- vasoconstrictor prostanoids and by reducing oxidative stress cytes (39, 114). Although DPP-4 inhibitors are promising anti- (85). Metformin confers cardioprotection against ischemia/ diabetic drugs, the cardiovascular effect of the DPP-4 inhibitors reprfusion injury through a PI3K-mediated inhibition of mi- in patients with T2DM remains to be investigated, because they tochondrial permeability transition pore opening (13). In induce postprandial hyperinsulinemia. Focussed here are two addition, metformin attenuated oxidative stress-induced representative insulin sensitizer, TZDs and metformin, because cardiomyocyte apoptosis and prevented the progression of these antidiabetic drugs have an established underlying heart failure in dogs, and this cardioprotective effect was mechanism for beneficial cardiovascular effects and have dependent on the activation of AMPK (123). Consistent with shown strong clinical evidence of reduced cardiovascular risk the beneficial cardiovascular effect in animals, the UK Pro- in patients with T2DM.
spective Diabetes Study (144a) showed that metformin de- The beneficial effect of TDZ is attributed to activation of creases macrovascular morbidity and mortality independent PPAR-c. A flurry of human and animal studies has shed a of glycemic control in patients with T2DM. A subsequent light on the mechanisms how TZDs act, and which of their randomized, placebo-controlled trial has demonstrated that physiological effects are dependent on PPAR-c. It is now ev- metformin can reduce inflammatory markers and improve ident that TDZ stimulates PPAR-c in adipocytes in the visceral endothelial function (35). The potential vascular protective adipose tissue and increases the generation of adiponectin (24, effects of metformin may complement other strategies within 126). Further, new roles for PPAR-c signaling beyond the such a framework. Thus, metformin treatment may represent metabolic effects through adiponectin have been discovered a relevant element of an integrated pharmacotherapy to pre- in inflammation, bone morphogenesis, endothelial function, vent not only T2DM but also cardiovascular disease in MetS.
cancer, longevity, and atherosclerosis (59). All of the majorcells in the vasculature express PPAR-c, including endothelial Antidyslipidemic agents cells, vascular SMCs, and monocytes/macrophages (40, 55).
PPAR-c is present in intimal macrophages in human athero- Because atherosclerosis is facilitated by dyslipidemia and mas (5). Recent experimental studies provide evidence that oxidative stress in patients with T2DM, numerous studies PPAR-c may function to protect the vasculature from injury have investigated relative contribution of dyslipidemia and (81, 103). Cell culture studies have shown that TZD inhibits oxidative stress to atherogenesis in diabetic animals. It has both the proliferation and migration of vascular SMCs (105).
been demonstrated that antioxidants vitamin E and probucol TZDs block vascular SMC growth by inducing cell cycle arrest and a 3-hydroxy-3-methylglutaryl Co-A reductase inhibitor in G1 through an inhibition of retinoblastoma protein phos- lovastatin significantly reduced plasma triglyceride in the phorylation (80). Migration of monocytes and vascular SMCs diabetic hamsters fed the atherogenic diet (42). In this study, is also inhibited by TZDs, possibly through decreased matrix vitamin E treatment increased total cholesterol, and probucol metalloproteinase production (108). Activation of PPAR-c by reduced HDL-cholesterol without affecting total cholesterol, TZDs in macrophages induces ATP binding cassette trans- whereas lovastatin reduced total cholesterol and selectively porter A1 expression to promote reverse cholesterol transport decreased non-HDL-cholestrerol, and significantly reduced (102). These effects of PPAR-c culminate in protection of en- fatty streak lesion formation in the aortic arch. Although vi- dothelial cells. Thus, TZD activation of PPAR-c may protect tamin E and probucol were effective in reducing several in- against atherosclerosis both by normalizing pro-atherogenic dices of oxidative stress, including plasma lipid peroxides, metabolic abnormalities of the insulin resistance/diabetes cholesterol oxidation products, and in vitro LDL oxidation, milieu and through an inhibition of vascular SMC growth and they had no effect on fatty streak lesion formation. These re- movement. Consistent with this hypothesis is the fact that in a sults indicate that the LDL in diabetic animals is more sus- large, placebo-controlled, outcome study in secondary pre- ceptible to oxidation than in nondiabetic hamsters and that vention, PROactive study, the use of pioglitazone in addition not only vitamin E and probucol but also lovastatin provide to an existing optimized macrovascular risk management antioxidant protection. It appears that in this combined model resulted in a significant reduction of macrovascular endpoints of T2DM and hypercholesterolemia, lovastatin prevented within a short observation period that was comparable to the progression of fatty streak lesion formation by reducing total effect of statins and ACE inhibitors in other trials (38). In ad- cholesterol and non-HDL-cholesterol and inhibiting oxidative dition, the efficacy of TDZs in preventing atherosclerosis in patients with T2DM has been confirmed by subsequent clin- The pleiotropic effects of statins that prevent atherogenesis ical trials (51). These results underline the value of TDZs for have been extensively investigated. Emerging evidence sug- managing the increased cardiovascular risk in MetS compli- gests that these cholesterol-independent effects are predomi- cated with T2DM.
nantly due to their ability to inhibit isoprenoid synthesis, Metformin is widely used as a hypoglycemic reagent for particularly geranylgeranylpyrophosphate and farnesylpyr- T2DM. The reduction of hepatic gluconeogenesis is thought to ophosphate, which are important post-translational lipid at- be a key effect of metformin, and its molecular mechanism is tachments of the Rho GTPases and activation of its attributed to the reduction of glucose-6-phosphatase activity, downstream target, Rho-kinase (ROCK) (117). Inhibition of as well as suppression of mRNA expression levels of multiple ROCK by statins may also be associated with inhibition of genes linked to the metabolic pathways involved in glucose oxidative stress mediated by activation of NADPH oxidase. It and lipid metabolism in the liver (60). However, metformin has been shown that rosuvastatin attenuated the Ang II- exerts cardiovascular protection independent of the blood mediated upregulation of NAPDH oxidase subunits as well as glucose-lowering efficacy. It has been demonstrated that nuclear factor-kappaB associated with downregulation of OXIDATIVE STRESS AND METABOLIC SYNDROME Ang II type-1 receptors and the lectin-like oxidized LDL re- that resveratrol confers protection against ischemia/reperfu- ceptor LOX-1, leading to the reduction of oxidized LDL (70).
sion injury through its antioxidant activity and upregulation of In this regard, while increased ROCK activity is associated NO production (56, 63, 116). Moreover, resveratrol modulates with endothelial dysfunction, cerebral ischemia and coronary vascular cell function, inhibits LDL oxidation, and suppresses vasospasms in MetS, the inhibition of ROCK by statins leads platelet aggregation (17). Miatello and associates (89) demon- to upregulation of eNOS, decreased vascular inflammation, strated that chronic administration of resveratrol prevented and reduced atherosclerotic plaque formation (165).
atherosclerosis in rats, and raised the hypothesis that the in- In MetS, increased triglyceride in conjunction with elevated crease in eNOS activity may contribute to the protective LDL plays a crucial role in atherogenesis. Such combined properties of resveratrol against cardiovascular disease. Re- dyslipidemia often requires multiple antidyslipidemic agents.
sults from other laboratories support the unifying hypothesis Fibrates effectively reduce fasting and postprandial hyper- that the improvements in risk factors by resveratrol are medi- triglycemia, shift the distribution of LDL particles toward less ated by eNOS (111, 118, 164). These results suggest that an dense particles, and increase HDL-cholesterol. The finding of adequate supplementation of resveratrol might help to prevent triglyceride-rich lipoproteins in human atheroma has pro- or delay the occurrence of atherogenic cardiovascular disease vided substantial pathophysiologic evidence for a direct role associated with insulin-resistant states in MetS. In addition, of triglyceride in atherogenesis (25, 58). Thus, fibrates repre- recent data provide interesting insights into the effect of re- sent particularly important tools to manage dyslipidemia in sveratrol on the lifespan of simple eukaryotes such as yeast and MetS complicated with T2DM. Indeed, compelling evidence flies by activating the longevity genes and has been suggested from meta-analysis of a number of clinical studies on a large as a CR mimetic (33, 62, 136, 155), implicating the potential of aggregate of patients has established an increased level of resveratrol as an antiaging agent in treating age-related human triglycerides as an independent risk factor for atherosclerotic diseases. This attractive property of resveratrol against ath- coronary heart disease (8, 52, 100). However, combination of erosclerosis and aging should be studied in human especially statins and fibrates is often contraindicated by increased in- in patients with MetS. However, the phenolic compound pos- cidence of myopathy. On the other hand, niacin, fibrates, and sesses a low bioavailability and rapid clearance from the bile acid sequestrants are effective in combination with statins plasma (29). Thus, bioavailability, metabolism, and tissue dis- in lowering LDL, triglycerides, and total cholesterol levels and tribution of resveratrol in humans need to be clearly estab- increasing HDL. Niacin-statin therapy reduces atherosclerotic lished to develop better biological effects.
progression and coronary events (10, 30, 34, 156). o-3 poly- Another potential pharmacological tool for the manage- unsaturated fatty acids, which are abundant in fish oil, are ment of cardiovascular risk factors in MetS is BH4. BH4 is a another promising tool for combination therapy for dyslipi- cofactor of eNOS, iNOS, and neuronal NOS and necessary for demic patients. The Japan Eicosapentaenoic Acid (EPA) Lipid NO biosynthesis. Lack of BH4 is associated with uncoupling Intervention Study demonstrated that EPA prevented major of NOS, leading to the generation of more superoxide and less coronary events, including sudden cardiac death, fatal and NO that shifts the nitroso-redox balance and may have ad- nonfatal myocardial infarction, and other nonfatal events, verse consequences on cardiovascular function. This trans- including unstable angina pectoris, angioplasty, stenting, or formation of NOS especially eNOS from a protective enzyme coronary artery bypass grafting in hypercholesterolemic pa- to a contributor to oxidative stress has been observed in sev- tients (161). The beneficial effect of EPA significantly corre- eral in vitro models, in animal models of cardiovascular dis- lated with the reduction of triglyceride and the increase in ease, and in patients with cardiovascular risk factors (45, 90, HDL (120), although cardiovascular protection by EPA may 91). BH4 is highly sensitive to oxidation by ROS and perox- also be attributed to the anti-inflammatory effect and inhibi- ynitrite and is converted to dihydrobiopterin (BH2). Oxida- tion of platelet function (93, 112). Taken all together, both tive stress imposed on endothelial cells causes depletion of triglyceride and HDL levels correlate with cardiovascular risk BH4 and eNOS uncoupling. In many cases, supplementation and should be considered secondary targets of therapy.
with BH4 under pathological conditions with oxidative stress Combination therapy can be safe and effective and can be has been shown to correct eNOS dysfunction in animal constructed to affect all lipoprotein parameters. However, models and patients (45, 90, 91). However, true mechanistic studies still are needed showing definite evidence on differ- relationship between endothelial BH4 levels and eNOS reg- ential therapy in lipid lowering based on prospective, con- ulation in vivo by administration of BH4 remains controver- trolled trials with endpoints of macro- and microangiopathy sial. High extracellular BH4 concentrations may result in in MetS complicated with T2DM and dyslipidemia.
nonspecific antioxidant effects that indirectly increase NObioactivity by ROS scavenging rather than by modulation ofeNOS activity. Further, the effects of supplementation with Other potential pharmacological tools BH4 or biopterin analogs on NO bioactivity are unpredictable Epidemiological studies suggest that the consumption of in vascular disease states in which oxidative stress is increased wine, particularly of red wine, reduces the incidence of mor- (140, 146). Indeed, it remains unclear whether adequate eNOS tality and morbidity from coronary heart disease. This has cofactor function in vivo is related to absolute BH4 levels in the given rise to what is now popularly termed the ‘‘French endothelial cell, or whether the relative balance between re- paradox'' (28). The cardioprotective effect has been attributed duced BH4 and oxidized BH2 may be more important (147).
to antioxidants present in the polyphenol fraction of red wine.
Intracellular BH4 levels are regulated by the activity of the Grapes contain a variety of antioxidants, including resveratrol, de novo biosynthetic pathway and the salvage pathway. In the catechin, epicatechin, and proanthocyanidins. Of these, re- de novo biosynthetic pathway, guanosine triphosphate cyclo- sveratrol is present mainly in grape skin, whereas proantho- hydrolase (GTPCH)-1 catalyzes GTP to dihydroneopterin cyanidin is present in the seeds. Emerging evidence indicates triphosphate. BH4 is generated by further steps catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reduc- ture of Japan and Promotion and Mutual Aid Corporation for tase (142). GTPCH-1 appears to be the rate-limiting enzyme in Private Schools of Japan.
BH4 biosynthesis; transgenic overexpression of GTPCH-1 issufficient to augment BH4 levels in endothelial cells and preserve NO-mediated endothelial function in diabetic mice(4). In the salvage pathway, BH4 is synthesized from BH2 by 1. This reference has been deleted.
sepiapterin reductase and dihydrofolate reductase. Exogen- 2. Alba AC and Delgado DH. Optimal medical treatment of cardiovascular risk factors: can we prevent the develop- ous BH4 is labile in physiological solution. It has been re- ment of heart failure? Expert Rev Cardiovasc Ther 7: 147– ported that in vivo half-life of BH4 is 3.3–5.1 h in the plasma of healthy adult humans (44). Because not all oxidized BH4 is 3. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, and converted to BH2, which is further degraded to dihydrox- Sadoshima J. Silent information regulator 2alpha, a lon- anthopterin and excreted to urine (129), BH2 availability for gevity factor and class III histone deacetylase, is an essen- the salvage pathway may be limited under oxidative stress tial endogenous apoptosis inhibitor in cardiac myocytes.
even with BH4 supplementation. Thus, sepiapterin may serve Circ Res 95: 971–980, 2004.
as an effective substrate for BH4 via the salvage pathway. Folic 4. Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, Goh acid and vitamin C are also able to restore eNOS functionality, N, Rockett KA, and Channon KM. Tetrahydrobiopterin- most probably by enhancing BH4 levels through mechanisms dependent preservation of nitric oxide-mediated endo- yet to be clarified (129). The therapeutic efficacy of BH4 has thelial function in diabetes by targeted transgenic been examined in patients with HTN, peripheral arterial dis- GTP-cyclohydrolase I overexpression. J Clin Invest 112: ease, and coronary artery disease, and these studies consis- 725–735, 2003.
tently demonstrated the beneficial effect of BH4 on endothelial 5. Amoruso A, Bardelli C, Fresu LG, Palma A, Vidali M, dysfunction (71). However, a phase-2 clinical trial sponsored Ferrero V, Ribichini F, Vassanelli C, and Brunelleschi S.
by the U.S. pharmaceutical company BioMarin failed to ob- serve an ameliorative effect of oral administration of BH4 in gamma expression in monocyte/macrophages from coro- patients with poorly controlled HTN. Further studies are nary artery disease patients and possible gender differences.
needed to address whether BH4 or its analogs truly exert sal- J Pharmacol Exp Ther 331: 531–538, 2009.
utary effects on endothelial dysfunction induced by a variety 6. Ando D, Hosaka Y, Suzuki K, and Yamagata Z. Effects of of vascular disease. Therapeutic opportunities for prevention exercise training on circulating high molecular weightadiponectin and adiponectin oligomer composition: a ran- of cardiovascular disease in MetS are illustrated in Figure 5.
domized controlled trial. J Atheroscler Thromb 16: 733–739,2009.
Concluding Remarks 7. Archuleta TL, Lemieux AM, Saengsirisuwan V, Teachey Abdominal obesity is a cause of all the morbidity of MetS.
MK, Lindborg KA, Kim JS, and Henriksen EJ. Oxidant Oxidative stress develops in hypertrophied adipocytes, which stress-induced loss of IRS-1 and IRS-2 proteins in rat skel- increase the synthesis of pro-inflammatory cytokines, while etal muscle: role of p38 MAPK. Free Radic Biol Med 47: decreasing anti-inflammatory cytokines. Dysregulation of 1486–1493, 2009.
such adipocytokines is responsible for systemic inflammation 8. Avogaro A, Giorda C, Maggini M, Mannucci E, Raschetti R, and oxidative stress and contributes to the pathogenesis of the Lombardo F, Spila-Alegiani S, Turco S, Velussi M, and obesity-associated morbidity in MetS. Decrease in abdominal Ferrannini E. Incidence of coronary heart disease in type 2diabetic men and women: impact of microvascular com- obesity by lifestyle interventions is fundamental approach to plications, treatment, and geographic location. Diabetes Care MetS. However, CR and exercise are often difficult in patients 30: 1241–1247, 2007.
with MetS. Thus, alternative strategies are required to prevent 9. Bartke A. Impact of reduced insulin-like growth factor-1/ cardiovascular risk in MetS. Accumulating basic research insulin signaling on aging in mammals: novel findings.
evidence indicates that endothelial cells are primarily affected Aging Cell 7: 285–290, 2008.
by inflammation and become a source of further oxidative 10. Bays H. Safety of niacin and simvastatin combination stress in the vascular wall and surrounding cells, leading to therapy. Am J Cardiol 101: 3B–8B, 2008.
IGT, HTN, and atherosclerosis. Thus, the endothelium is 11. Bendall JK, Alp NJ, Warrick N, Cai S, Adlam D, Rockett K, recognized as a major therapeutic target in the prevention and Yokoyama M, Kawashima S, and Channon KM. Stoichio- treatment of vascular disease in patients with MetS. The purpose of improving endothelial function is to restore nor- biopterin, endothelial NO synthase (eNOS) activity, and mal biosynthesis of NO and the reduction of excessive gen- eNOS coupling in vivo: insights from transgenic mice with eration of ROS. Currently available pharmacological tools endothelial-targeted GTP cyclohydrolase 1 and eNOS over- such as ACE inhibitors, ARBs, TDZs, metformin, and statins expression. Circ Res 97: 864–871, 2005.
are effective in preventing cardiovascular risk in MetS 12. Berg AH and Scherer PE. Adipose tissue, inflammation, through reduction of inflammation and oxidative stress either and cardiovascular disease. Circ Res 96: 939–949, 2005.
in the visceral adipose tissue or endothelial cells. Further 13. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva studies are needed to develop more effective strategy to M, Wynne AM, Mocanu MM, and Yellon DM. Metformin manage cardiovascular risk in MetS.
protects the ischemic heart by the Akt-mediated inhibitionof mitochondrial permeability transition pore opening.
Basic Res Cardiol 103: 274–284, 2008.
14. Bitar MS, Al-Saleh E, and Al-Mulla F. Oxidative stress— This work was supported in part by Research Grant mediated alterations in glucose dynamics in a genetic ani- 20590847 from the Ministry of Education, Science, and Cul- mal model of type II diabetes. Life Sci 77: 2552–2573, 2005.
OXIDATIVE STRESS AND METABOLIC SYNDROME 15. Bluher M. Fat tissue and long life. Obes Facts 1: 176–182, 34. Davidson MH and Toth PP. Combination therapy in the management of complex dyslipidemias. Curr Opin Lipidol 16. Boyle JJ. Macrophage activation in atherosclerosis: patho- 15: 423–431, 2004.
genesis and pharmacology of plaque rupture. Curr Vasc 35. De Jager J, Kooy A, Lehert P, Bets D, Wulffele MG, Teerlink Pharmacol 3: 63–68, 2005.
T, Scheffer PG, Schalkwijk CG, Donker AJ, and Stehouwer 17. Bradamante S, Barenghi L, and Villa A. Cardiovascular CD. Effects of short-term treatment with metformin on protective effects of resveratrol. Cardiovasc Drug Rev 22: markers of endothelial function and inflammatory activity 169–188, 2004.
in type 2 diabetes mellitus: a randomized, placebo-con- 18. Bradley RL, Jeon JY, Liu FF, and Maratos-Flier E. Voluntary trolled trial. J Intern Med 257: 100–109, 2005.
exercise improves insulin sensitivity and adipose tissue 36. Dickhout JG, Hossain GS, Pozza LM, Zhou J, Lhotak S, and inflammation in diet-induced obese mice. Am J Physiol Austin RC. Peroxynitrite causes endoplasmic reticulum Endocrinol Metab 295: E586–E594, 2008.
stress and apoptosis in human vascular endothelium: im- 19. Brozinick JT, Jr., Roberts BR, and Dohm GL. Defective plications in atherogenesis. Arterioscler Thromb Vasc Biol 25: signaling through Akt-2 and - 3 but not Akt-1 in insulin- 2623–2629, 2005.
resistant human skeletal muscle: potential role in insulin 37. DiCorleto PE. Cellular mechanisms of atherogenesis. Am J resistance. Diabetes 52: 935–941, 2003.
Hypertens 6: 314S–318S, 1993.
20. Bulcao C, Ferreira SR, Giuffrida FM, and Ribeiro-Filho FF.
38. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, The new adipose tissue and adipocytokines. Curr Diabetes Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Le- Rev 2: 19–28, 2006.
febvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, 21. Carling D, Sanders MJ, and Woods A. The regulation of Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, AMP-activated protein kinase by upstream kinases. Int J Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen Obes (Lond) 32 Suppl 4: S55–S59, 2008.
A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, 22. Cassis LA, Police SB, Yiannikouris F, and Thatcher SE.
Smith U, and Taton J. Secondary prevention of macro- Local adipose tissue renin-angiotensin system. Curr Hy- vascular events in patients with type 2 diabetes in the pertens Rep 10: 93–98, 2008.
PROactive Study (PROspective pioglitAzone Clinical Trial 23. Chen B, Wei J, Wang W, Cui G, Zhao Y, Zhu X, Zhu M, In macroVascular Events): a randomised controlled trial.
Guo W, and Yu J. Identification of signaling pathways in- Lancet 366: 1279–1289, 2005.
volved in aberrant production of adipokines in adipocytes 39. Doupis J and Veves A. DPP4 inhibitors: a new approach in undergoing oxidative stress. Arch Med Res 40: 241–248, diabetes treatment. Adv Ther 25: 627–643, 2008.
40. Duan SZ, Usher MG, and Mortensen RM. Peroxisome 24. Choi KC, Ryu OH, Lee KW, Kim HY, Seo JA, Kim SG, Kim proliferator-activated receptor-gamma-mediated effects in NH, Choi DS, Baik SH, and Choi KM. Effect of PPAR-alpha the vasculature. Circ Res 102: 283–294, 2008.
and -gamma agonist on the expression of visfatin, adipo- 41. Duda DG, Fukumura D, and Jain RK. Role of eNOS in nectin, and TNF-alpha in visceral fat of OLETF rats. Bio- neovascularization: NO for endothelial progenitor cells.
chem Biophys Res Commun 336: 747–753, 2005.
Trends Mol Med 10: 143–145, 2004.
25. Choy PC, Siow YL, Mymin D, and O K. Lipids and ath- 42. El-Swefy S, Schaefer EJ, Seman LJ, van Dongen D, Sevanian erosclerosis. Biochem Cell Biol 82: 212–224, 2004.
A, Smith DE, Ordovas JM, El-Sweidy M, and Meydani M.
26. Collot-Teixeira S, Martin J, McDermott-Roe C, Poston R, The effect of vitamin E, probucol, and lovastatin on oxi- and McGregor JL. CD36 and macrophages in atheroscle- dative status and aortic fatty lesions in hyperlipidemic- rosis. Cardiovasc Res 75: 468–477, 2007.
diabetic hamsters. Atherosclerosis 149: 277–286, 2000.
27. Colman RJ, Anderson RM, Johnson SC, Kastman EK, 43. Evans JL, Maddux BA, and Goldfine ID. The molecular Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons basis for oxidative stress-induced insulin resistance. Anti- HA, Kemnitz JW, and Weindruch R. Caloric restriction oxid Redox Signal 7: 1040–1052, 2005.
delays disease onset and mortality in rhesus monkeys.
44. Fiege B, Ballhausen D, Kierat L, Leimbacher W, Goriounov Science 325: 201–204, 2009.
D, Schircks B, Thony B, and Blau N. Plasma tetra- 28. Constant J. Alcohol, ischemic heart disease, and the French hydrobiopterin and its pharmacokinetic following oral paradox. Coron Artery Dis 8: 645–649, 1997.
administration. Mol Genet Metab 81: 45–51, 2004.
29. Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, and 45. Forstermann U and Munzel T. Endothelial nitric oxide Beaudeux JL. Resveratrol bioavailability and toxicity in synthase in vascular disease: from marvel to menace. Cir- humans. Mol Nutr Food Res 54: 7–16.
culation 113: 1708–1714, 2006.
30. Cziraky MJ, Watson KE, and Talbert RL. Targeting low 46. Forsythe LK, Wallace JM, and Livingstone MB. Obesity and HDL-cholesterol to decrease residual cardiovascular risk in inflammation: the effects of weight loss. Nutr Res Rev 21: the managed care setting. J Manag Care Pharm 14: S3–S28; 117–133, 2008.
quiz S30–S21, 2008.
47. Fujioka S, Matsuzawa Y, Tokunaga K, and Tarui S. Con- 31. Dandona P, Dhindsa S, Ghanim H, and Chaudhuri A.
tribution of intra-abdominal fat accumulation to the im- Angiotensin II and inflammation: the effect of angiotensin- pairment of glucose and lipid metabolism in human converting enzyme inhibition and angiotensin II receptor obesity. Metabolism 36: 54–59, 1987.
blockade. J Hum Hypertens 21: 20–27, 2007.
48. Fukui T, Rahman M, Hayashi K, Takeda K, Higaki J, Sato 32. Das M, Gabriely I, and Barzilai N. Caloric restriction, body T, Fukushima M, Sakamoto J, Morita S, Ogihara T, fat and ageing in experimental models. Obes Rev 5: 13–19, Fukiyama K, Fujishima M, and Saruta T. Candesartan an- tihypertensive survival evaluation in Japan (CASE-J) trial 33. Dasgupta B and Milbrandt J. Resveratrol stimulates AMP of cardiovascular events in high-risk hypertensive patients: kinase activity in neurons. Proc Natl Acad Sci U S A 104: rationale, design, and methods. Hypertens Res 26: 979–990, 7217–7222, 2007.
49. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada 63. Hung LM, Chen JK, Huang SS, Lee RS, and Su MJ.
Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Cardioprotective effect of resveratrol, a natural antioxi- and Shimomura I. Increased oxidative stress in obesity and dant derived from grapes. Cardiovasc Res 47: 549–555, its impact on metabolic syndrome. J Clin Invest 114: 1752– 64. Hung YC, Hong MY, and Huang GS. Cholesterol loading 50. Gao YJ, Takemori K, Su LY, An WS, Lu C, Sharma AM, and augments oxidative stress in macrophages. FEBS Lett 580: Lee RM. Perivascular adipose tissue promotes vasocon- 849–861, 2006.
striction: the role of superoxide anion. Cardiovasc Res 71: 65. Igarashi M, Hirata A, Yamaguchi H, Tsuchiya H, Ohnuma 363–373, 2006.
H, Tominaga M, Daimon M, and Kato T. Candesartan in- 51. Goldberg RB. The new clinical trials with thiazolidine- hibits carotid intimal thickening and ameliorates insulin diones—DREAM, ADOPT, and CHICAGO: promises ful- resistance in balloon-injured diabetic rats. Hypertension 38: filled? Curr Opin Lipidol 18: 435–442, 2007.
1255–1259, 2001.
52. Goldenberg I, Benderly M, Sidi R, Boyko V, Tenenbaum A, 66. Inoguchi T and Nawata H. NAD(P)H oxidase activation: a Tanne D, and Behar S. Relation of clinical benefit of raising potential target mechanism for diabetic vascular compli- high-density lipoprotein cholesterol to serum levels of low- cations, progressive beta-cell dysfunction and metabolic density lipoprotein cholesterol in patients with coronary syndrome. Curr Drug Targets 6: 495–501, 2005.
heart disease (from the bezafibrate infarction prevention 67. Jelic S and Le Jemtel TH. Inflammation, oxidative stress, trial). Am J Cardiol 103: 41–45, 2009.
and the vascular endothelium in obstructive sleep apnea.
53. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Trends Cardiovasc Med 18: 253–260, 2008.
Bushnell CD, Culebras A, DeGraba TJ, Gorelick PB, Guyton 68. Kadowaki T and Yamauchi T. Adiponectin and adipo- JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, and nectin receptors. Endocr Rev 26: 439–451, 2005.
Sacco RL. Primary prevention of ischemic stroke: a guide- 69. Kalinowski L and Malinski T. Endothelial NADH/ line from the American Heart Association/American NADPH-dependent enzymatic sources of superoxide pro- Stroke Association Stroke Council: cosponsored by the duction: relationship to endothelial dysfunction. Acta Bio- chim Pol 51: 459–469, 2004.
disciplinary Working Group; Cardiovascular Nursing 70. Kang BY and Mehta JL. Rosuvastatin attenuates Ang II— Council; Clinical Cardiology Council; Nutrition, Physical mediated cardiomyocyte hypertrophy via inhibition of Activity, and Metabolism Council; and the Quality of Care LOX-1. J Cardiovasc Pharmacol Ther 14: 283–291, 2009.
and Outcomes Research Interdisciplinary Working Group.
71. Katusic ZS, d'Uscio LV, and Nath KA. Vascular protection Circulation 113: e873–e923, 2006.
by tetrahydrobiopterin: progress and therapeutic pros- 54. Greenstein AS, Khavandi K, Withers SB, Sonoyama K, pects. Trends Pharmacol Sci 30: 48–54, 2009.
Clancy O, Jeziorska M, Laing I, Yates AP, Pemberton PW, 72. Kim Y and Lee S. Physical activity and abdominal obesity Malik RA, and Heagerty AM. Local inflammation and in youth. Appl Physiol Nutr Metab 34: 571–581, 2009.
hypoxia abolish the protective anticontractile properties of 73. Koh KK, Oh PC, and Quon MJ. Does reversal of oxidative perivascular fat in obese patients. Circulation 119: 1661– stress and inflammation provide vascular protection? Car- diovasc Res 81: 649–659, 2009.
55. Hamblin M, Chang L, Fan Y, Zhang J, and Chen YE. PPARs 74. Kurata A, Nishizawa H, Kihara S, Maeda N, Sonoda M, and the cardiovascular system. Antioxid Redox Signal 11: Okada T, Ohashi K, Hibuse T, Fujita K, Yasui A, Hiuge A, 1415–1452, 2009.
Kumada M, Kuriyama H, Shimomura I, and Funahashi T.
56. Hattori R, Otani H, Maulik N, and Das DK. Pharmaco- Blockade of angiotensin II type-1 receptor reduces oxida- logical preconditioning with resveratrol: role of nitric tive stress in adipose tissue and ameliorates adipocytokine oxide. Am J Physiol Heart Circ Physiol 282: H1988–H1995, dysregulation. Kidney Int 70: 1717–1724, 2006.
75. Lara-Castro C, Luo N, Wallace P, Klein RL, and Garvey 57. Hattori Y, Akimoto K, Gross SS, Hattori S, and Kasai K.
WT. Adiponectin multimeric complexes and the metabolic Angiotensin-II-induced oxidative stress elicits hypoadipo- syndrome trait cluster. Diabetes 55: 249–259, 2006.
nectinaemia in rats. Diabetologia 48: 1066–1074, 2005.
76. Lau DC, Dhillon B, Yan H, Szmitko PE, and Verma S.
58. Heeren J, Beisiegel U, and Grewal T. Apolipoprotein E re- Adipokines: molecular links between obesity and ather- cycling: implications for dyslipidemia and atherosclerosis.
oslcerosis. Am J Physiol Heart Circ Physiol 288: H2031– Arterioscler Thromb Vasc Biol 26: 442–448, 2006.
H2041, 2005.
59. Heikkinen S, Auwerx J, and Argmann CA. PPARgamma in 77. Lavie L, and Lavie P. Molecular mechanisms of cardio- human and mouse physiology. Biochim Biophys Acta 1771: vascular disease in OSAHS: the oxidative stress link. Eur 999–1013, 2007.
Respir J 33: 1467–1484, 2009.
60. Heishi M, Ichihara J, Teramoto R, Itakura Y, Hayashi K, 78. Le Brocq M, Leslie SJ, Milliken P, and Megson IL. En- Ishikawa H, Gomi H, Sakai J, Kanaoka M, Taiji M, and dothelial dysfunction: from molecular mechanisms to Kimura T. Global gene expression analysis in liver of obese measurement, clinical implications, and therapeutic op- diabetic db/db mice treated with metformin. Diabetologia portunities. Antioxid Redox Signal 10: 1631–1674, 2008.
49: 1647–1655, 2006.
79. Libby P. The molecular mechanisms of the thrombotic 61. Holloszy JO and Fontana L. Caloric restriction in humans.
complications of atherosclerosis. J Intern Med 263: 517–527, Exp Gerontol 42: 709–712, 2007.
62. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu 80. Lim HJ, Lee S, Park JH, Lee KS, Choi HE, Chung KS, S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Lee HH, and Park HY. PPAR delta agonist L-165041 in- Scherer B, and Sinclair DA. Small molecule activators of hibits rat vascular smooth muscle cell proliferation and sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: migration via inhibition of cell cycle. Atherosclerosis 202: 191–196, 2003.
446–454, 2009.
OXIDATIVE STRESS AND METABOLIC SYNDROME 81. Lim S, Jin CJ, Kim M, Chung SS, Park HS, Lee IK, Lee CT, 98. Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Cho YM, Lee HK, and Park KS. PPARgamma gene transfer Sica V, and Ignarro LJ. Nitric oxide and atherosclerosis: an sustains apoptosis, inhibits vascular smooth muscle cell update. Nitric Oxide 15: 265–279, 2006.
proliferation, and reduces neointima formation after bal- 99. Nawrocki AR, Hofmann SM, Teupser D, Basford JE, Dur- loon injury in rats. Arterioscler Thromb Vasc Biol 26: 808–813, and JL, Jelicks LA, Woo CW, Kuriakose G, Factor SM, Tanowitz HB, Hui DY, Tabas I, and Scherer PE. Lack of 82. Luque Contreras D, Vargas Robles H, Romo E, Rios A, and association between adiponectin levels and atherosclerosis Escalante B. The role of nitric oxide in the post-ischemic in mice. Arterioscler Thromb Vasc Biol 30: 1159–1165, 2010.
revascularization process. Pharmacol Ther 112: 553–563, 100. Nesto RW. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the 83. Magkos F, Mohammed BS, and Mittendorfer B. Enhanced metabolic syndrome. Am J Cardiovasc Drugs 5: 379–387, insulin sensitivity after acute exercise is not associated with changes in high-molecular weight adiponectin concentra- 101. Numao S, Suzuki M, Matsuo T, Nomata Y, Nakata Y, tion in plasma. Eur J Endocrinol 162: 61–66, 2010.
and Tanaka K. Effects of acute aerobic exercise on high- 84. Martinet W and Kockx MM. Apoptosis in atherosclerosis: molecular-weight adiponectin. Med Sci Sports Exerc 40: focus on oxidized lipids and inflammation. Curr Opin Li- 1271–1276, 2008.
pidol 12: 535–541, 2001.
102. Ogata M, Tsujita M, Hossain MA, Akita N, Gonzalez FJ, 85. Matsumoto T, Noguchi E, Ishida K, Kobayashi T, Yamada Staels B, Suzuki S, Fukutomi T, Kimura G, and Yokoyama N, and Kamata K. Metformin normalizes endothelial S. On the mechanism for PPAR agonists to enhance ABCA1 function by suppressing vasoconstrictor prostanoids in gene expression. Atherosclerosis 205: 413–419, 2009.
mesenteric arteries from OLETF rats, a model of type 2 103. Ogawa D, Nomiyama T, Nakamachi T, Heywood EB, diabetes. Am J Physiol Heart Circ Physiol 295: H1165–H1176, Stone JF, Berger JP, Law RE, and Bruemmer D. Activation of peroxisome proliferator-activated receptor gamma sup- 86. Matsunami T, Sato Y, Ariga S, Sato T, Kashimura H, Ha- presses telomerase activity in vascular smooth muscle cells.
segawa Y, and Yukawa M. Regulation of oxidative stress Circ Res 98: e50–e59, 2006.
and inflammation by hepatic adiponectin receptor 2 in an 104. Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Sho- animal model of nonalcoholic steatohepatitis. Int J Clin Exp jima N, Ono H, Fujishiro M, Kushiyama A, Fukushima Y, Pathol 3: 472–481, 2010.
Kikuchi M, Noguchi N, Aburatani H, Gotoh Y, Komuro I, 87. Maury E and Brichard SM. Adipokine dysregulation, adi- and Fujita T. Oxidative stress induces insulin resistance by pose tissue inflammation and metabolic syndrome. Mol Cell activating the nuclear factor-kappa B pathway and dis- Endocrinol 314: 1–16, 2010.
rupting normal subcellular distribution of phosphatidyli- 88. Miard S and Picard F. Obesity and aging have diver- nositol 3-kinase. Diabetologia 47: 794–805, 2004.
gent genomic fingerprints. Int J Obes (Lond) 32: 1873–1874, 105. Okura T, Nakamura M, Takata Y, Watanabe S, Kitami Y, and Hiwada K. Troglitazone induces apoptosis via the p53 89. Miatello R, Vazquez M, Renna N, Cruzado M, Zumino AP, and Gadd45 pathway in vascular smooth muscle cells. Eur and Risler N. Chronic administration of resveratrol pre- J Pharmacol 407: 227–235, 2000.
vents biochemical cardiovascular changes in fructose-fed 106. Otabe S, Yuan X, Fukutani T, Wada N, Hashinaga T, Na- rats. Am J Hypertens 18: 864–870, 2005.
kayama H, Hirota N, Kojima M, and Yamada K. Over- 90. Moens AL and Kass DA. Tetrahydrobiopterin and cardio- expression of human adiponectin in transgenic mice results vascular disease. Arterioscler Thromb Vasc Biol 26: 2439– in suppression of fat accumulation and prevention of pre- mature death by high-calorie diet. Am J Physiol Endocrinol 91. Moens AL and Kass DA. Therapeutic potential of tetra- Metab 293: E210–E218, 2007.
hydrobiopterin for treating vascular and cardiac disease. J 107. Otani H. Ischemic preconditioning: from molecular mech- Cardiovasc Pharmacol 50: 238–246, 2007.
anisms to therapeutic opportunities. Antioxid Redox Signal 92. Monroe VS, Kerensky RA, Rivera E, Smith KM, and Pepine 10: 207–247, 2008.
CJ. Pharmacologic plaque passivation for the reduction of 108. Pakala R, Dilcher C, Baffour R, Hellinga D, Seabron R, recurrent cardiac events in acute coronary syndromes. J Am Joner M, Kolodgie F, Virmani R, and Waksman R. Peroxi- Coll Cardiol 41: 23S–30S, 2003.
some proliferator-activated receptor gamma ligand piogli- 93. Mori TA and Beilin LJ. Omega-3 fatty acids and inflam- tazone alters neointimal composition in a balloon-denuded mation. Curr Atheroscler Rep 6: 461–467, 2004.
and radiated hypercholesterolemic rabbit. J Cardiovasc 94. Muller G and Morawietz H. Nitric oxide, NAD(P)H oxi- Pharmacol 48: 299–305, 2006.
dase, and atherosclerosis. Antioxid Redox Signal 11: 1711– 109. Paradis S, Ailion M, Toker A, Thomas JH, and Ruvkun G.
A PDK1 homolog is necessary and sufficient to transduce 95. Muoio DM and Newgard CB. Metabolism: A is for adi- AGE-1 PI3 kinase signals that regulate diapause in Cae- pokine. Nature 436: 337–338, 2005.
norhabditis elegans. Genes Dev 13: 1438–1452, 1999.
96. Muzumdar R, Allison DB, Huffman DM, Ma X, Atzmon G, 110. Peake PW, Shen Y, Walther A, and Charlesworth JA.
Einstein FH, Fishman S, Poduval AD, McVei T, Keith SW, Adiponectin binds C1q and activates the classical pathway and Barzilai N. Visceral adipose tissue modulates mam- of complement. Biochem Biophys Res Commun 367: 560–565, malian longevity. Aging Cell 7: 438–440, 2008.
97. Myllarniemi M, Calderon L, Lemstrom K, Buchdunger E, 111. Penumathsa SV, Thirunavukkarasu M, Koneru S, Juhasz B, and Hayry P. Inhibition of platelet-derived growth factor Zhan L, Pant R, Menon VP, Otani H, and Maulik N. Statin receptor tyrosine kinase inhibits vascular smooth muscle and resveratrol in combination induces cardioprotection cell migration and proliferation. FASEB J 11: 1119–1126, against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol 42: 508–516, 2007.
112. Phang M, Garg ML, and Sinclair AJ. Inhibition of 127. Shepherd PR and Kahn BB. Glucose transporters and in- platelet aggregation by omega-3 polyunsaturated fatty sulin action—implications for insulin resistance and dia- acids is gender specific-Redefining platelet response to betes mellitus. N Engl J Med 341: 248–257, 1999.
fish oils. Prostaglandins Leukot Essent Fatty Acids 81: 35– 128. Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Lau- bach VE, Sherman PA, Sessa WC, and Smithies O. Elevated 113. Picard F and Guarente L. Molecular links between aging blood pressures in mice lacking endothelial nitric oxide and adipose tissue. Int J Obes (Lond) 29 Suppl 1: S36–S39, synthase. Proc Natl Acad Sci U S A 93: 13176–13181, 1996.
129. Shi W, Meininger CJ, Haynes TE, Hatakeyama K, and Wu 114. Quast U, Stephan D, Bieger S, and Russ U. The impact of G. Regulation of tetrahydrobiopterin synthesis and bio- ATP-sensitive K + channel subtype selectivity of insulin availability in endothelial cells. Cell Biochem Biophys 41: secretagogues for the coronary vasculature and the myo- 415–434, 2004.
cardium. Diabetes 53 Suppl 3: S156–S164, 2004.
130. Shinmura K, Tamaki K, and Bolli R. Impact of 6-mo caloric 115. Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen restriction on myocardial ischemic tolerance: possible in- SL, and Silverstein RL. A CD36-dependent signaling cas- volvement of nitric oxide-dependent increase in nuclear cade is necessary for macrophage foam cell formation. Cell Sirt1. Am J Physiol Heart Circ Physiol 295: H2348–H2355, 2008.
Metab 4: 211–221, 2006.
131. Shinmura K, Tamaki K, Saito K, Nakano Y, Tobe T, and Bolli 116. Ray PS, Maulik G, Cordis GA, Bertelli AA, Bertelli A, and R. Cardioprotective effects of short-term caloric restriction are Das DK. The red wine antioxidant resveratrol protects mediated by adiponectin via activation of AMP-activated isolated rat hearts from ischemia reperfusion injury. Free protein kinase. Circulation 116: 2809–2817, 2007.
Radic Biol Med 27: 160–169, 1999.
132. Skultetyova D, Filipova S, Riecansky I, and Skultety J. The 117. Rikitake Y and Liao JK. Rho GTPases, statins, and nitric role of angiotensin type 1 receptor in inflammation and oxide. Circ Res 97: 1232–1235, 2005.
endothelial dysfunction. Recent Pat Cardiovasc Drug Discov 118. Rivera L, Moron R, Zarzuelo A, and Galisteo M. Long-term 2: 23–27, 2007.
resveratrol administration reduces metabolic disturbances 133. Soares AF, Guichardant M, Cozzone D, Bernoud-Hubac N, and lowers blood pressure in obese Zucker rats. Biochem Bouzaidi-Tiali N, Lagarde M, and Geloen A. Effects of Pharmacol 77: 1053–1063, 2009.
oxidative stress on adiponectin secretion and lactate pro- 119. Ruige JB, Assendelft WJ, Dekker JM, Kostense PJ, Heine RJ, duction in 3T3-L1 adipocytes. Free Radic Biol Med 38: 882– and Bouter LM. Insulin and risk of cardiovascular disease: a meta-analysis. Circulation 97: 996–1001, 1998.
134. Staiger H and Haring HU. Adipocytokines: fat-derived 120. Saito Y, Yokoyama M, Origasa H, Matsuzaki M, Matsu- humoral mediators of metabolic homeostasis. Exp Clin zawa Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura Endocrinol Diabetes 113: 67–79, 2005.
H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, 135. Stauss HM, Godecke A, Mrowka R, Schrader J, and Persson and Shirato K. Effects of EPA on coronary artery disease in PB. Enhanced blood pressure variability in eNOS knockout hypercholesterolemic patients with multiple risk factors: mice. Hypertension 33: 1359–1363, 1999.
sub-analysis of primary prevention cases from the Japan 136. Swindell WR. Comparative analysis of microarray data EPA Lipid Intervention Study ( JELIS). Atherosclerosis 200: identifies common responses to caloric restriction among 135–140, 2008.
mouse tissues. Mech Ageing Dev 129: 138–153, 2008.
121. Sakurai T, Izawa T, Kizaki T, Ogasawara JE, Shirato K, 137. Tabas I. Apoptosis and efferocytosis in mouse models of Imaizumi K, Takahashi K, Ishida H, and Ohno H. Exercise atherosclerosis. Curr Drug Targets 8: 1288–1296, 2007.
training decreases expression of inflammation-related adi- 138. Tamori Y, Sakaue H, and Kasuga M. RBP4, an unexpected pokines through reduction of oxidative stress in rat white adipokine. Nat Med 12: 30–31; discussion 31, 2006.
adipose tissue. Biochem Biophys Res Commun 379: 605–609, 139. Tao L, Gao E, Jiao X, Yuan Y, Li S, Christopher TA, Lopez BL, Koch W, Chan L, Goldstein BJ, and Ma XL. Adipo- 122. Sarzani R, Salvi F, Dessi-Fulgheri P, and Rappelli A. Renin- angiotensin system, natriuretic peptides, obesity, metabolic reperfusion involves the reduction of oxidative/nitrative syndrome, and hypertension: an integrated view in hu- stress. Circulation 115: 1408–1416, 2007.
mans. J Hypertens 26: 831–843, 2008.
140. Tarpey MM. Sepiapterin treatment in atherosclerosis. Ar- 123. Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, terioscler Thromb Vasc Biol 22: 1519–1521, 2002.
Ito S, Ogai A, Asakura M, Kim J, Minamino T, Takashima 141. Thomas SR, Witting PK, and Drummond GR. Redox con- S, Sanada S, Sugimachi M, Komamura K, Mochizuki N, trol of endothelial function and dysfunction: molecular and Kitakaze M. Metformin prevents progression of heart mechanisms and therapeutic opportunities. Antioxid Redox failure in dogs: role of AMP-activated protein kinase. Cir- Signal 10: 1713–1765, 2008.
culation 119: 2568–2577, 2009.
142. Thony B, Auerbach G, and Blau N. Tetrahydrobiopterin 124. Scheen AJ. Prevention of type 2 diabetes mellitus through biosynthesis, regeneration and functions. Biochem J 347 Pt 1: inhibition of the Renin-Angiotensin system. Drugs 64: 1–16, 2000.
2537–2565, 2004.
143. Thorne RF, Mhaidat NM, Ralston KJ, and Burns GF. CD36 125. Schulz E, Jansen T, Wenzel P, Daiber A, and Munzel T.
is a receptor for oxidized high density lipoprotein: impli- Nitric oxide, tetrahydrobiopterin, oxidative stress, and en- cations for the development of atherosclerosis. FEBS Lett dothelial dysfunction in hypertension. Antioxid Redox Signal 581: 1227–1232, 2007.
10: 1115–1126, 2008.
144. Thorp E and Tabas I. Mechanisms and consequences of 126. Sharma AM and Staels B. Review: peroxisome proliferator- efferocytosis in advanced atherosclerosis. J Leukoc Biol 86: activated receptor gamma and adipose tissue—understanding 1089–1095, 2009.
obesity-related changes in regulation of lipid and glucose 144a.UK Prospective Diabetes Study (UKPDS) Group. Effect of metabolism. J Clin Endocrinol Metab 92: 386–395, 2007.
intensive blood-glucose control with metformin on com- OXIDATIVE STRESS AND METABOLIC SYNDROME plications in overweight patients with type 2 diabetes drome in obese individuals: the impact of rapid weight loss (UKPDS 34). Lancet 352: 854–865, 1998.
through caloric restriction. J Clin Endocrinol Metab 89: 2697– 145. Vanhoutte PM. Endothelial dysfunction: the first step to- ward coronary arteriosclerosis. Circ J 73: 595–601, 2009.
159. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida 146. Vasquez-Vivar J, Duquaine D, Whitsett J, Kalyanaraman B, S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, and Rajagopalan S. Altered tetrahydrobiopterin metabo- Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, lism in atherosclerosis: implications for use of oxidized Kahn BB, and Kadowaki T. Adiponectin stimulates glucose tetrahydrobiopterin analogues and thiol antioxidants. Ar- utilization and fatty-acid oxidation by activating AMP- terioscler Thromb Vasc Biol 22: 1655–1661, 2002.
activated protein kinase. Nat Med 8: 1288–1295, 2002.
147. Vasquez-Vivar J, Martasek P, Whitsett J, Joseph J, and 160. Yassine HN, Marchetti CM, Krishnan RK, Vrobel TR, Kalyanaraman B. The ratio between tetrahydrobiopterin Gonzalez F, and Kirwan JP. Effects of exercise and caloric and oxidized tetrahydrobiopterin analogues controls su- restriction on insulin resistance and cardiometabolic risk peroxide release from endothelial nitric oxide synthase: an factors in older obese adults—a randomized clinical trial. J EPR spin trapping study. Biochem J 362: 733–739, 2002.
Gerontol A Biol Sci Med Sci 64: 90–95, 2009.
148. Vieira VJ, Valentine RJ, Wilund KR, Antao N, Baynard T, 161. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, and Woods JA. Effects of exercise and low-fat diet on adi- Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura pose tissue inflammation and metabolic complications in H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, obese mice. Am J Physiol Endocrinol Metab 296: E1164–E1171, and Shirato K. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients ( JELIS): 149. Vinayagamoorthi R, Bobby Z, and Sridhar MG. Anti- a randomised open-label, blinded endpoint analysis. Lancet oxidants preserve redox balance and inhibit c-Jun-N- 369: 1090–1098, 2007.
terminal kinase pathway while improving insulin signaling 162. You T and Nicklas BJ. Effects of exercise on adipokines and in fat-fed rats: evidence for the role of oxidative stress on the metabolic syndrome. Curr Diab Rep 8: 7–11, 2008.
IRS-1 serine phosphorylation and insulin resistance. J En- 163. Zafon C. Fat and aging: a tale of two tissues. Curr Aging Sci docrinol 197: 287–296, 2008.
2: 83–94, 2009.
150. Viollet B, Guigas B, Leclerc J, Hebrard S, Lantier L, Mounier 164. Zhang H, Zhang J, Ungvari Z, and Zhang C. Resveratrol R, Andreelli F, and Foretz M. AMP-activated protein kinase improves endothelial function: role of TNF{alpha} and in the regulation of hepatic energy metabolism: from vascular oxidative stress. Arterioscler Thromb Vasc Biol 29: physiology to therapeutic perspectives. Acta Physiol (Oxf) 1164–1171, 2009.
196: 81–98, 2009.
165. Zhou Q and Liao JK. Rho kinase: an important mediator of 151. Wainwright CL. Matrix metalloproteinases, oxidative stress atherosclerosis and vascular disease. Curr Pharm Des 15: and the acute response to acute myocardial ischaemia and 3108–3115, 2009.
reperfusion. Curr Opin Pharmacol 4: 132–138, 2004.
166. Zhu M, Lee GD, Ding L, Hu J, Qiu G, de Cabo R, Bernier M, 152. Waki H and Tontonoz P. Endocrine functions of adipose Ingram DK, and Zou S. Adipogenic signaling in rat white tissue. Annu Rev Pathol 2: 31–56, 2007.
adipose tissue: modulation by aging and calorie restriction.
153. Wang G, Woo CW, Sung FL, Siow YL, and O K. Increased Exp Gerontol 42: 733–744, 2007.
monocyte adhesion to aortic endothelium in rats with hy- 167. Zhu M, Miura J, Lu LX, Bernier M, DeCabo R, Lane MA, perhomocysteinemia: role of chemokine and adhesion Roth GS, and Ingram DK. Circulating adiponectin levels molecules. Arterioscler Thromb Vasc Biol 22: 1777–1783, 2002.
increase in rats on caloric restriction: the potential for in- 154. Wang Y, Gao E, Tao L, Lau WB, Yuan Y, Goldstein BJ, sulin sensitization. Exp Gerontol 39: 1049–1059, 2004.
Lopez BL, Christopher TA, Tian R, Koch W, and Ma XL.
168. Ziemke F and Mantzoros CS. Adiponectin in insulin re- AMP-activated protein kinase deficiency enhances myo- sistance: lessons from translational research. Am J Clin Nutr cardial ischemia/reperfusion injury but has minimal effect 91: 258S–261S.
on the antioxidant/antinitrative protection of adiponectin.
Circulation 119: 835–844, 2009.
155. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, and Sinclair D. Sirtuin activators mimic caloric restric- Address correspondence to: tion and delay ageing in metazoans. Nature 430: 686–689, Second Department of Internal Medicine 156. Worz CR and Bottorff M. Treating dyslipidemic patients Kansai Medical University with lipid-modifying and combination therapies. Pharma- cotherapy 23: 625–637, 2003.
Moriguchi City 570-8507 157. Wu HC, Chen SY, Shroff SG, and Carroll JD. Stress analysis using anatomically realistic coronary tree. Med Phys 30:2927–2936, 2003.
158. Xydakis AM, Case CC, Jones PH, Hoogeveen RC, Liu MY, Smith EO, Nelson KW, and Ballantyne CM. Adiponectin, Date of first submission to ARS Central, November 4, 2010; inflammation, and the expression of the metabolic syn- date of acceptance, December 2, 2010.
Abbreviations Used iNOS ¼ inducible nitric oxide synthase ACE ¼ angiotensin-converting enzyme IRS ¼ insulin receptor substrate ACEI ¼ angiotensin-converting inhibitor LDL ¼ low-density lipoprotein AMPK ¼ AMP-activated protein kinase MCP-1 ¼ monocyte chemoattractant protein-1 Ang II ¼ angiotensin II MetS ¼ metabolic syndrome ARBs ¼ angiotensin II type-1 receptor blockers NO ¼ nitric oxide BH2 ¼ dihydrobiopterin OxLDL ¼ oxidized LDL BH4 ¼ tetrahydrobiopterin PAI-1 ¼ plasminogen activator inhibitor-1 CR ¼ caloric restriction PI3K ¼ phosphatidylinositol 3-kinase DPP-4 ¼ dipeptidyl peptidase-IV PPAR ¼ peroxisome proliferator activated receptor eNOS ¼ endothelial nitric oxide synthase RAAS ¼ renin-angiotensin aldosterone system EPA ¼ eicosapentaenoic acid ROCK ¼ Rho-kinase GLUT4 ¼ glucose transporter-4 ROS ¼ reactive oxygen species GTPCH ¼ guanosine triphosphate cyclohydrolase SMCs ¼ smooth muscle cells HDL ¼ high-density lipoprotein T2DM ¼ type-2 diabetes mellitus HTN ¼ hypertension TDZs ¼ thiazolidinediones IGT ¼ impaired glucose tolerance TNF-a ¼ tumor necrosis factor-a This article has been cited by:
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