The histone deacetylase SIRT1 is a key regulator of cardiovascular oxidative stress

Dr. Li, Huige, Dr. Xia, Ning, Dr. Daiber, Andreas, Habermeier, Alice, Spanier, Gerrit , Lu, Qing , Dr. Oelze, Matthias, Prof. Dr. Closs, Ellen I., Prof. Dr. Münzel, Thomas, Prof. Dr. Förstermann, Ulrich. Johannes Gutenberg University Department of Pharmacology, Obere Zahlbacher Str. 67, 55131 Mainz, Germany.

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 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 guanosine 5’-triphosphate (GTP) via a de novo pathway by the rate-limiting enzyme GTP cyclohydrolase I (GCH1), and essential for eNOS functionality. ApoE-KO mice are associated with 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. Also in human endothelial EA.hy 926 cells, resveratrol (100 µM) upregulated SOD1-3, GPx1 and catalase, and downregulated NOX4. SIRT1 inhibition with sirtinol or SIRT1 knockdown by siRNA blocked part of the effects of resveratrol. These data indicate that SIRT1 is a key regulator of cardiovascular oxidative stress.