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

Abstract

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.

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…Delivery of adenoviral vectors encoding SIRT1 into the hearts of diabetic rats markedly increased SIRT1 expression and was accompanied by a reduced cardiomyocyte apoptosis, superoxide generation, and by a simultaneous eNOS activation (46). SIRT1 protects blood vessels from hyperglycemiainduced endothelial dysfunction through a mechanism involving the downregulation of p66…”

SIRT1 exerts neuroprotective effects by attenuating cerebral ischemia/reperfusion-induced injury via targeting p53/microRNA-22

“…Collectively, our results suggested that SIRT1 may prove to be an important therapeutic target for the treatment of CIRI. Ding et al also suggested that SIRT1 protected against myocardial ischemia-reperfusion injury in diabetic rats (23).…”

Punicalagin Pretreatment Attenuates Myocardial Ischemia-Reperfusion Injury via Activation of AMPK

“…The LAD artery was retied after the 6 h of reperfusion and myocardial infarct size (INF) was evaluated by Evans Blue/triphenyltetrazolium chloride (TTC) staining as we described before (Ding et al, 2015). Evans blue (2%) was perfused through the aorta to stain the myocardial area not at risk.…”

“…Superoxide generation in heart tissue was determined as we described previously (Ding et al, 2015) by lucigenin-enhanced chemiluminescence. The results were indicated as relative light units (RLU) per milligram dry weight per second (RLU/mg/s).…”