Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy / 中华医学杂志(英文版)

ABSTRACT

<p><b>BACKGROUND</b>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.</p><p><b>METHODS</b>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 blotting.</p><p><b>RESULTS</b>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 < 0.05).</p><p><b>CONCLUSIONS</b>Our findings indicate that the antioxidant alpha-LA can effectively attenuate mitochondria-dependent cardiac apoptosis and exert a protective role against the development of diabetic cardiomyopathy. The ability of alpha-LA to suppress mitochondrial oxidative damage is concomitant with an enhancement of Mn-SOD activity and an increase in the GSH content of myocardial mitochondria.</p>