Rapid, Direct Effects of Statin Treatment on Arterial Redox State and Nitric Oxide Bioavailability in Human Atherosclerosis via Tetrahydrobiopterin-Mediated Endothelial Nitric Oxide Synthase Coupling

Abstract

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

Adiponectin as a Link Between Type 2 Diabetes and Vascular NADPH Oxidase Activity in the Human Arterial Wall: The Regulatory Role of Perivascular Adipose Tissue

“…Vascular O 2 _ 2 production was measured in fresh, intact IMA segments by using lucigenin-enhanced chemiluminescence, as previously described (20). NADPH oxidase activity was estimated by quantifying the NADPH-stimulated O 2 _ 2 in these vessels, and the specificity of this measurement was assessed by using the specific NADPH oxidase inhibitor Vas2870.…”

“…To examine the direct effects of adiponectin on NADPH oxidase activity in human IMA segments, we used a wellvalidated ex vivo model of human vessels that we have previously described (20). For these experiments, we recruited 67 additional patients undergoing CABG surgery following the same exclusion criteria as for study 1.…”

The Effect of Lowering LDL Cholesterol on Vascular Access Patency

“…After formation, successful access maturation requires vessel outward remodeling, a process that statins may also promote by increasing endothelial nitric oxide availability (23,28). However, in SHARP, it was only possible to test reliably for any benefit on preexisting (prevalent) vascular access.…”

Genetic predisposition in patients with hypertension and normal ejection fraction to oxidative stress

“…Statins and other drugs, such as renin-angiotensin system inhibitors and beta blockers, used in the treatment of hypertension might have decreased OXS in patients with hypertension compared to controls due to their antioxidant effect 34,35 .…”