SIRT1 protects against myocardial ischemia–reperfusion injury via activating eNOS in diabetic rats

Cardiovascular Diabetology

Original Investigation

Jingyi Lei¹  Xiaoming Wang²  Yinxian Qu³  Weibo Li³  Hongcheng Han³  Mingge Ding⁴  Feng Fu⁵  Enqing Fu⁶ 

[1] Department of Cardiology, Xi’an Central Hospital, 710000, Xi’an, China;Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, 710032, Xi’an, China;Department of Geriatrics, Xi’an Central Hospital, 710000, Xi’an, China;Department of Geriatrics, Xi’an Central Hospital, 710000, Xi’an, China;Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, 710032, Xi’an, China;Department of Physiology, Fourth Military Medical University, 169 Changlexi Road, 710032, Xi’an, China;Department of Respiratory Medicine, Tangdu Hospital, Fourth Military Medical University, 710032, Xi’an, China;

关键词: SIRT1;    Ischemia–reperfusion;    Diabetes;    Oxidative stress;    eNOS;   

DOI  :  10.1186/s12933-015-0299-8

 received in 2015-08-05, accepted in 2015-09-30,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundDiabetic patients are more sensitive to myocardial ischemic injury than non-diabetic patients. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase making the heart more resistant to ischemic injury. As SIRT1 expression is considered to be reduced in diabetic heart, we therefore hypothesized that up-regulation of SIRT1 in the diabetic heart may overcome its increased susceptibility to ischemic injury.MethodsMale Sprague–Dawley rats were fed with high-fat diet and injected with streptozotocin once to induce diabetes. Diabetic rats received injections of adenoviral vectors encoding SIRT1 (Ad-SIRT1) at five myocardial sites. Four days after adenoviral injection, the rats were subjected to myocardial ischemia and reperfusion (MI/R). Outcome measures included left ventricular function, infarct size, cellular death and oxidative stress.ResultsDelivery of Ad-SIRT1 into the hearts of diabetic rats markedly increased SIRT1 expression. Up-regulation of SIRT1 in diabetic hearts improved cardiac function and reduced infarct size to the extent as in non-diabetic animals following MI/R, which was associated with reduced serum creatine kinase-MB, lactate dehydrogenase activities and cardiomyocyte apoptosis. Moreover, Ad-SIRT1 reduced the increase in the superoxide generation and malonaldialdehyde content and simultaneously increased the antioxidant capability. Furthermore, Ad-SIRT1 increased eNOS phosphorylation and reduced eNOS acetylation in diabetic hearts. NOS inhibitor L-NAME inhibited SIRT1-enhanced eNOS phosphorylation, and blunted SIRT1-mediated anti-apoptotic and anti-oxidative effects and cardioprotection.ConclusionsOverexpression of SIRT1 reduces diabetes-exacerbated MI/R injury and oxidative stress via activating eNOS in diabetic rats. The findings suggest SIRT1 may be a promising novel therapeutic target for diabetic cardiac complications.

【 授权许可】

CC BY   
© Ding et al. 2015