Background-Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states.We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis. Methods and Results-The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O 2 − ) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O 2 − production/ eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O 2 − and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism. Conclusions-We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue. (Circulation. 2013;127:2209-2221.)

Background-Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. Methods and Results-We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O 2 ·Ϫ ) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O 2 ·Ϫ generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O 2 ·Ϫ generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-L-arginine methyl ester-inhibitable O 2 ·Ϫ in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O 2 ·Ϫ . These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. Conclusions-This

Atherosclerosis, the main pathophysiological condition leading to cardiovascular disease (CVD), is now considered to be a chronic inflammatory condition. Statins are the most widely used and promising agents in treating CVD and are renowned for their pleiotropic lipid-lowering independent effects. Statins exert their anti-inflammatory effects on the vascular wall through a variety of molecular pathways of the innate and adaptive immune systems, their impact on the circulating levels of pro-inflammatory cytokines, and their effect on adhesion molecules. By inhibiting the mevalonate pathway and isoprenoid formation, statins account for the increase of nitric oxide bioavailability and the improvement of vascular and myocardial redox state by multiple different mechanisms (directly or indirectly through low-density lipoprotein [LDL] lowering). A large number of randomized control trials have shown that statins help in the primary and secondary prevention of cardiovascular events, not only via their lipid-lowering effect, but also due to their anti-inflammatory potential as well. In this paper, we examine the molecular pathways in which statins are implicated and exert their anti-inflammatory effects, and we focus specifically on their impact on innate and adaptive immunity systems. Finally, we review the most important clinical data for the role of statins in primary and secondary prevention of cardiovascular events.