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.

Objective-To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease. Approach and Results-In a cross-sectional study of 575 subjects, serum adiponectin was compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-α, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy individuals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged. Conclusions-This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.

There is a strong independent association between myocardial O(2)(-)/ONOO(-) and in-hospital complications after cardiac surgery. Both myocardial O(2)(-) and ONOO(-) are reduced by pre-operative statin treatment, through a Rac1-mediated suppression of NADPH oxidase activity. These findings suggest that inhibition of myocardial NADPH oxidases may contribute to the beneficial effect of statins in patients undergoing cardiac surgery. (Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients; NCT01013103).

Background-Statins

Abstract-We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (nϭ11 healthy and nϭ60 CAD) or placebo (nϭ11 healthy and nϭ10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (PϽ0.0001 for both). However, interleukin 6 was inversely correlated with FMD (PϽ0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (rϭ0.515; PϽ0.0001) compared with CAD (rϭ0.289; Pϭ0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (PϽ0.0001) and ADMA (Pϭ0.004) but lower FMD (Pϭ0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (PϽ0.001) and CAD (PϽ0.001) subjects. FMD was reduced in healthy subjects (PϽ0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (PϽ0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans. (Hypertension. 2011;58:93-98.) • Online Data Supplement Key Words: ADMA Ⅲ endothelium Ⅲ inflammation Ⅲ interleukin 6 Ⅲ atherosclerosis Ⅲ coronary artery disease T he development of endothelial dysfunction is considered to be the initial step in atherogenesis. 1 A healthy endothelium is responsible for NO generation through oxidation of L-arginine by endothelial NO synthase (eNOS). 1 NO maintains vascular tone and acts, per se, as an important intracellular messenger, inducing divergent anti-inflammatory, antithrombotic, and antiapoptotic effects. 1 Asymmetrical dimethylarginine (ADMA), an endogenous L-arginine analog, has been associated with impaired endothelial function in humans. 2 ADMA has also been associated with eNOS uncoupling that results in increased eNOSderived superoxide production in human vessels. 2 Clinical evidence suggests that ADMA plasma levels are associated with endothelial function, particularly in patients with coronary atherosclerosis 3 or atherosclerosis risk factors, 4 whereas this association is significant but weak in healthy individuals. 5 Furthermore, in prospective studies, plasma ADMA has been independently associated with clinical outcome and mortality in diabetic subjects and patients with atherosclerosis. 6 ADMA is derived from ...

Background-The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is essential for maintenance of enzymatic function. We hypothesized that induction of BH4 synthesis might be an endothelial defense mechanism against inflammation in vascular disease states. Methods and Results-In Study 1, 20 healthy individuals were randomized to receive Salmonella typhi vaccine (a model of acute inflammation) or placebo in a double-blind study. Vaccination increased circulating BH4 and interleukin 6 and induced endothelial dysfunction (as evaluated by brachial artery flow-mediated dilation) after 8 hours. In Study 2, a functional haplotype (X haplotype) in the GCH1 gene, encoding GTP-cyclohydrolase I, the rate-limiting enzyme in biopterin biosynthesis, was associated with endothelial dysfunction in the presence of high-sensitivity C-reactive protein in 440 coronary artery disease patients. In Study 3, 10 patients with coronary artery disease homozygotes for the GCH1 X haplotype (XX) and 40 without the haplotype (OO) underwent S Typhi vaccination. XX patients were unable to increase plasma BH4 and had a greater reduction of flow-mediated dilation than OO patients. In Study 4, vessel segments from 19 patients undergoing coronary bypass surgery were incubated with or without cytokines (interleukin-6/tumor necrosis factor-␣/lipopolysaccharide) for 24 hours. Cytokine stimulation upregulated GCH1 expression, increased vascular BH4, and improved vasorelaxation in response to acetylcholine, which was inhibited by the GTP-cyclohydrolase inhibitor 2,4-diamino-6-hydroxypyrimidine. Conclusions-The ability to increase vascular GCH1 expression and BH4 synthesis in response to inflammation preserves endothelial function in inflammatory states. These novel findings identify BH4 as a vascular defense mechanism against inflammation-induced endothelial dysfunction.