SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats.
SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats.
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DOI：
10.1186/s12933-015-0299-8
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发表时间：
2015-10-21
影响因子：
9.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Ding M;Lei J;Han H;Li W;Qu Y;Fu E;Fu F;Wang X
糖尿病患者比非糖尿病患者对心肌缺血性损伤更敏感。沉默信息调节因子 1 (SIRT1) 是一种烟酰胺腺嘌呤二核苷酸依赖性组蛋白脱乙酰酶，使心脏更能抵抗缺血性损伤。由于 SIRT1 表达被认为在糖尿病心脏中降低，因此我们假设糖尿病心脏中 SIRT1 的上调可能克服其对缺血性损伤的易感性增加。雄性Sprague-Dawley大鼠采用高脂饮食喂养并注射链脲佐菌素一次以诱发糖尿病。糖尿病大鼠在五个心肌部位接受编码 SIRT1 (Ad-SIRT1) 的腺病毒载体注射。注射腺病毒四天后，对大鼠进行心肌缺血再灌注（MI/R）。结果指标包括左心室功能、梗塞面积、细胞死亡和氧化应激。将 Ad-SIRT1 递送到糖尿病大鼠的心脏中显着增加了 SIRT1 的表达。糖尿病心脏中 SIRT1 的上调改善了心功能并减少了梗塞面积，其程度与 MI/R 后的非糖尿病动物相同，这与血清肌酸激酶 MB、乳酸脱氢酶活性和心肌细胞凋亡的减少有关。此外，Ad-SIRT1减少了超氧化物生成和丙二醛含量的增加，同时增加了抗氧化能力。此外，Ad-SIRT1 增加糖尿病心脏中的 eNOS 磷酸化并减少 eNOS 乙酰化。 NOS 抑制剂 L-NAME 抑制 SIRT1 增强的 eNOS 磷酸化，并减弱 SIRT1 介导的抗凋亡和抗氧化作用以及心脏保护作用。 SIRT1 的过度表达通过激活糖尿病大鼠的 eNOS 来减少糖尿病加剧的 MI/R 损伤和氧化应激。研究结果表明 SIRT1 可能是糖尿病心脏并发症的一个有前途的新型治疗靶点。
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. 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. 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. 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.