The metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality. Studies are needed to investigate whether or not the prognostic significance of the metabolic syndrome exceeds the risk associated with the sum of its individual components. Furthermore, studies are needed to elucidate the mechanisms by which the metabolic syndrome increases cardiovascular risk.

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Abstract-Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease. Key Words: atherosclerosis Ⅲ hypertension Ⅲ kidney Ⅲ vasculature I t is increasingly apparent that individuals with chronic kidney disease (CKD) are more likely to die of cardiovascular (CV) disease (CVD) than to develop kidney failure. 1,2 A large cohort study comprising Ͼ130 000 elderly subjects showed that increased incidence of CV events could be in part related to the fact that persons with renal insufficiency are less likely to receive appropriate cardioprotective treatments. 3 However, beyond the effects of lack of appropriate therapy, it is clear that accelerated CVD is prevalent in subjects with CKD. The first part of the present review will therefore focus on the epidemiological links between impairment of renal function and adverse CV events, between albuminuria and CV events, and between serum cystatin C and CVD. The second part of the present review will address the mechanisms that lead to the association of renal and CVD, which include hypertension, dyslipidemia, activation of the renin-angiotensin system, endothelial dysfunction and the role of asymmetric dimethyl arginine (ADMA), oxidative stress, and inflammation. Finally, mechanisms that are involved in vascular calcification often found in CKD and end-stage renal disease (ESRD) will be described. Additionally, ESRD is associated with several specific complications caused by the uremic state per se, which can contribute to the development and progression of CVD through volume overload with consequent hypertension, anemia, uremic pericarditis, and cardiomyopathy. However, these issues will not be addressed because the emphasis will be on CKD before ESRD is reached. In addition, t...

Reactive oxygen species (ROS), including superoxide (*O2-), hydrogen peroxide (H2O2), and hydroxyl anion (OH-), and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite (ONOO-), are biologically important O2 derivatives that are increasingly recognized to be important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) produce ROS, primarily via cell membrane-associated NAD(P)H oxidase. Reactive oxygen species regulate vascular function by modulating cell growth, apoptosis/anoikis, migration, inflammation, secretion, and extracellular matrix protein production. An imbalance in redox state where pro-oxidants overwhelm anti-oxidant capacity results in oxidative stress. Oxidative stress and associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, including hypertension, hyperlipidemia, and diabetes. Increased generation of ROS has been demonstrated in experimental and human hypertension. Anti-oxidants and agents that interrupt NAD(P)H oxidase-driven *O2- production regress vascular remodeling, improve endothelial function, reduce inflammation, and decrease blood pressure in hypertensive models. This experimental evidence has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage. The present chapter focuses on the importance of ROS in vascular biology and discusses the role of oxidative stress in vascular damage in hypertension.

Abstract-Angiotensin-(1-7) [Ang-(1-7)] causes endothelial-dependent vasodilation mediated, in part, by NO release.However, the molecular mechanisms involved in endothelial NO synthase (eNOS) activation by Ang-(1-7) remain unknown. Using Chinese hamster ovary cells stably transfected with Mas cDNA (Chinese hamster ovary-Mas), we evaluated the underlying mechanisms related to receptor Mas-mediated posttranslational eNOS activation and NO release. We further examined the Ang-(1-7) profile of eNOS activation in human aortic endothelial cells, which constitutively express the Mas receptor. Chinese hamster ovary-Mas cells and human aortic endothelial cell were stimulated with Ang-(1-7; 10 Ϫ7 mol/L; 1 to 30 minutes) in the absence or presence of A-779 (10 Ϫ6 mol/L). Additional experiments were performed in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin (10 Ϫ6 mol/L). Changes in eNOS (at Ser1177/Thr495 residues) and Akt phosphorylation were evaluated by Western blotting. NO release was measured using both the fluorochrome 2,3-diaminonaphthalene and an NO analyzer. Ang-(1-7) significantly stimulated eNOS activation (reciprocal phosphorylation/dephosphorylation at Ser1177/Thr495) and induced a sustained Akt phosphorylation (PϽ0.05). Concomitantly, a significant increase in NO release was observed (2-fold increase in relation to control). These effects were blocked by A-779. Wortmannin suppressed eNOS activation in both Chinese hamster ovary-Mas and human aortic endothelial cells. Our findings demonstrate that Ang-(1-7), through Mas, stimulates eNOS activation and NO production via Akt-dependent pathways. These novel data highlight the importance of the Ang-(1-7)/Mas axis as a putative regulator of endothelial function. T he renin-angiotensin system is a crucial regulator of cardiovascular homeostasis. Most physiological effects of angiotensin (Ang) II are mediated via Ang II type 1 (AT 1 ) receptors (AT 1 R), with Ang II type 2 (AT 2 ) receptors (AT 2 R) counteracting AT 1 R actions. 1 Growing evidence indicates that the Ang peptide Ang-(1-7) plays an important role in the renin-angiotensin system. 2 This heptapeptide is formed by Ang-converting enzyme-dependent and Ang-converting enzyme-independent pathways. Much attention has been given recently to its formation through hydrolysis of Ang II by the ectoenzyme Ang-converting enzyme 2, which is present in many organs. 3 Ang-(1-7) opposes many Ang II-stimulated actions. Ang-(1-7), acting through the G protein-coupled receptor (GPCR) Mas, releases NO and prostaglandins causing vasodilation, inhibition of cell growth, and opposition of AT 1 R-mediated Ang II vasoconstrictor and proliferative effects. 2 Overactivity of the renin-angiotensin system, as observed in cardiovascular diseases, and the lack of balance among its peptides may reduce NO bioavailability leading to endothelial dysfunction. 4,5 NO plays a critical role in endothelial function, maintaining vasodilator tone, inhibiting platelet aggregation and adhesion, and modulating vascular smooth ...

Abstract-A major source of vascular smooth muscle cell (VSMC) superoxide is NAD(P)H oxidase. However, the molecular characteristics and regulation of this enzyme are unclear. We investigated whether VSMCs from human resistance arteries (HVSMCs) possess a functionally active, angiotensin II (Ang II)-regulated NAD(P)H oxidase that contains neutrophil oxidase subunits, including p22phox, gp91phox, p40phox, p47phox, and p67phox. mRNA expression of gp91phox homologues, nox1 and nox4, was also assessed in HVSMCs, human aortic smooth muscle cells, and rat VSMCs. HVSMCs were obtained from resistance arteries from gluteal biopsies of healthy subjects. gp91phox and nox4, but not nox1, were detected in HVSMCs. Nox1 and nox4, but not gp91phox, were expressed in human aortic smooth muscle cells and rat VSMCs. All NAD(P)H oxidase subunits were present in HVSMCs as detected by reverse transcriptase-polymerase chain reaction and immunoblotting. Ang II increased NAD(P)H oxidase subunit abundance. These effects were inhibited by cycloheximide. Acute Ang II stimulation (10 to 15 minutes) increased p47phox serine phosphorylation and induced p47phox and p67phox translocation. This was associated with NAD(P)H oxidase activation. In cells transfected with gp91phox antisense oligonucleotides, Ang II-mediated actions were abrogated. NADPH-induced superoxide generation was reduced by gp91ds-tat and apocynin, inhibitors of p47phox-gp91phox interactions. Our results suggest that HVSMCs possess a functionally active gp91phox-containing neutrophil-like NAD(P)H oxidase. Ang II regulates the enzyme by inducing phosphorylation of p47phox, translocation of cytosolic subunits, and de novo protein synthesis. These novel findings provide insight into the molecular regulation of NAD(P)H oxidase by Ang II in HVSMCs. Furthermore, we identify differences in gp91phox homologue expression in VSMCs from rats and human small and large arteries.

The AT(1) antagonist losartan corrected the altered structure and endothelial dysfunction of resistance arteries from patients with essential hypertension, whereas the beta-blocker atenolol had no effect.