SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats.
BACKGROUND
Diabetic 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.


METHODS
Male 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.


RESULTS
Delivery 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.


CONCLUSIONS
Overexpression 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.
Department of Geriatrics, Xi'an Central Hospital, Xi'an, 710000, China. minggeding@163.com.|Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China. minggeding@163.com.
Mingge
M
Ding
Department of Cardiology, Xi'an Central Hospital, Xi'an, 710000, China. 362304743@qq.com.
Jingyi
J
Lei
Department of Geriatrics, Xi'an Central Hospital, Xi'an, 710000, China. 435411499@qq.com.
Hongcheng
H
Han
Department of Geriatrics, Xi'an Central Hospital, Xi'an, 710000, China. 906144831@qq.com.
Weibo
W
Li
Department of Geriatrics, Xi'an Central Hospital, Xi'an, 710000, China. 18991246091@126.com.
Yinxian
Y
Qu
Department of Respiratory Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China. fmmufuenqing@126.com.
Enqing
E
Fu
Department of Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032, China. fufeng048@126.com.
Feng
F
Fu
Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China. xmwang@fmmu.edu.cn.
Xiaoming
X
Wang
D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000235:genetics
D004791:Enzyme Inhibitors; D013481:Superoxides; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D052279:Creatine Kinase, MB Form; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D019331:NG-Nitroarginine Methyl Ester