Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy
Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy
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DOI：
10.3760/cma.j.issn.0366-6999.2009.21.010
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发表时间：
2009-11-05
影响因子：
6.1
通讯作者：
Yu De-min
中科院分区：
文献类型：
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作者：
Li Chun-jun;Zhang Qiu-mei;Yu De-min
背景心力衰竭是糖尿病患者死亡的主要原因。这在一定程度上是由于一种特殊的心肌病，称为糖尿病心肌病。氧化应激被广泛认为是该病发病的主要因素之一。本研究旨在探讨抗氧化剂α-硫辛酸(α-LA)能否通过抑制线粒体氧化应激而减轻线粒体依赖性心肌细胞凋亡，从而减轻糖尿病心肌病变。方法采用链脲佐菌素(STZ)45 mg/kg尾静脉注射复制糖尿病大鼠模型。实验动物随机分为3组：正常对照组(NC)、糖尿病组(DM)和糖尿病加α-LA组(α-LA)。后一组给予α-LA(100 mg/kg，ip/d)，其余组给予等量溶媒。在糖尿病发病后4、8和12周，用原位末端标记法检测心肌细胞凋亡。通过对心脏结构和功能的评估来评价心肌病。通过测定心肌线粒体中丙二醛(MDA)、还原型谷胱甘肽(GSH)含量和锰超氧化物歧化酶(Mn-SOD)活性来评价氧化损伤程度。结果糖尿病发病后4、8、12周，α-LA组TUNEL阳性细胞数、caspase-9、-3表达及线粒体细胞色素c释放量均明显低于DM组。DM组大鼠心肌线粒体丙二醛含量显著升高，线粒体GSH含量和Mn-SOD活性均显著降低。经α-LA治疗后，这些症状明显改善。HE染色显示了糖尿病心脏的结构异常，而α-LA逆转了这种结构紊乱。糖尿病组心功能指数(+/-dp/dtmax)在4~12周呈进行性加重，而α-LA延缓心功能恶化(P
Background Cardiac failure is a leading cause of the mortality of diabetic patients. In part this is due to a specific cardiomyopathy, referred to as diabetic cardiomyopathy. Oxidative stress is widely considered to be one of the major factors underlying the pathogenesis of the disease. This study aimed to test whether the antioxidant alpha-lipoic acid (alpha-LA) could attenuate mitochondrion-dependent myocardial apoptosis through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy.Methods A rat model of diabetes was induced by a single tail intravenous injection of streptozotocin (STZ) 45 mg/kg. Experimental animals were randomly assigned to 3 groups: normal control (NC), diabetes (DM) and DM treated with alpha-LA (alpha-LA). The latter group was administered with alpha-LA (100 mg/kg ip per day), the remainder received the same volume vehicle. At weeks 4, 8, and 12 after the onset of diabetes, cardiac apoptosis was examined by TUNEL assay. Cardiomyopathy was evaluated by assessment of cardiac structure and function. Oxidative damage was evaluated by the content of malondialdehyde (MDA), reduced glutathione (GSH) and the activity of manganese superoxide diamutase (Mn-SOD) in the myocardial mitochondria. Expression of caspase-9 and caspase-3 proteins was determined by immunohistochemistry and mitochondrial cytochrome c release was detected by Western blottingResults At 4, 8, and 12 weeks after the onset of diabetes, significant reductions in TUNEL-positive cells, caspase-9,-3 expression, and mitochondrial cytochrome c release were observed in the alpha-LA group compared to the DM group. In the DM group, the content of MDA in the myocardial mitochondria was significantly increased, and there was a decrease in both the mitochondrial GSH content and the activities of Mn-SOD. They were significantly improved by alpha-LA treatment. HE staining displayed structural abnormalities in diabetic hearts, while alpha-LA reversed this structural derangement. The index of cardiac function (+/- dp/dtmax) in the diabetes group was aggravated progressively from 4 weeks to 12 weeks, but alpha-LA delayed deterioration of cardiac function (P