Abstract
SIRT1 is a NAD+-dependent class III histone deacetylase. Recent studies point to SIRT1 as a key regulator of angiogenesis, vascular tone and endothelial function. The aim of the present study was to investigate the role of SIRT1 in regulating oxidative stress in the cardiovascular system. Atherosclerotic apolipoprotein E knockout (ApoE-KO) mice were treated with a SIRT1 activator, resveratrol (30 or 100 mg/kg/day for 7 days via gavage). Resveratrol treatment significantly reduced the levels of 3-nitrotyrosine, malondialdehyde and superoxide in the heart, which was associated with an upregulation of superoxide dismutase isoforms (SOD1–3), glutathione peroxidase 1 (GPx1), and catalase. In parallel, mRNA expression of NADPH oxidase subunits NOX2 and NOX4 was reduced. Resveratrol also inhibited the translocation of p47phox and Rac1 and decreased the activity of NADPH oxidase complex in heart membrane fraction. The cofactor of endothelial nitric oxide synthase (eNOS), (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), is synthesized from GTP via a de novo pathway by the rate-limiting enzyme GTP cyclohydrolase I (GCH1), and essential for eNOS functionality. ApoE-KO mice showed increased oxidative stress and eNOS-mediated superoxide production (i.e. eNOS uncoupling). Treatment of ApoE-KO mice with resveratrol enhanced the expression of GCH1 and increased the cardiac levels of BH4. This was associated with reduced superoxide production from eNOS. To find out whether the observed effects of resveratrol were SIRT-dependent, human endothelial EA.hy 926 cells were treated with resveratrol. Also in these cells, resveratrol treatment led to an upregulation of SOD1–3, GPx1, catalase, GCH1, and a downregulation of NOX4. SIRT1 inhibition with sirtinol or SIRT1 knockdown by siRNA reduced the effects of resveratrol on SOD1, SOD2, GPx1, GCH1, but not those on SOD3, catalase, or NOX4. These data indicate that resveratrol reduces cardiovascular oxidative stress by decreasing superoxide production from NADPH oxidases and uncoupled eNOS, and by enhancing superoxide inactivation by SOD isoforms and catalase. Part of the resveratrol effects are SIRT1-dependent. Thus, SIRT1 is likely a novel target for treatment of cardiovascular disease.
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