Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy.
Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy.
复制标题
早期给予曲美他嗪可通过减轻纤维化、减少细胞凋亡和增强自噬来减轻大鼠糖尿病心肌病
DOI：
10.1186/s12967-016-0849-1
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发表时间：
2016-04-27
影响因子：
7.4
通讯作者：
Zhang W
中科院分区：
文献类型：
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作者：
Zhang L;Ding WY;Wang ZH;Tang MX;Wang F;Li Y;Zhong M;Zhang Y;Zhang W
曲美他嗪作为一种抗缺血、抗氧化剂，具有多种心脏保护作用。然而，早期给予曲美他嗪是否对糖尿病性心肌病有影响，其作用机制尚未阐明。MethodsWe建立了2型DCM大鼠模型，高脂饮食和低剂量链脲佐菌素。将大鼠分为不同的组：对照组、糖尿病组和糖尿病+曲美他嗪组（每组n = 6）。心脏自噬，心脏功能，心肌细胞凋亡monitored.ResultsRats与2型DCM表现出严重的胰岛素抵抗，左心室功能不全，心肌细胞凋亡增加，减少心脏自噬。胶原体积分数（CVF）和血管周围胶原面积/管腔面积（PVCA/LA）比值在糖尿病组显著高于对照组。我们发现，曲美他嗪治疗改善代谢紊乱和胰岛素抵抗，减少心肌细胞凋亡，恢复心脏自噬。糖尿病+曲美他嗪组的CVF和PVCA/LA比值也低于糖尿病组（CVF为4.75 ± 0.52%vs.11.04 ± 1.67%，p< 0.05; PVCA/LA为8.37 ± 0.51vs.17.97 ± 2.66，p < 0.05）。此外，曲美他嗪抑制ERK和P38 MAPK的磷酸化，以减轻心肌纤维化。糖尿病+曲美他嗪组AMPK磷酸化恢复，Bcl-2与Beclin 1相互作用增强，启动自噬，减轻细胞凋亡。结论早期给予曲美他嗪可通过抑制心肌纤维化和心肌细胞凋亡，增强自噬来改善糖尿病心肌病。因此，在糖尿病早期应用曲美他嗪可能是预防糖尿病心肌病的一个很好的选择。
BackgroundTrimetazidine, as an anti-ischemic and antioxidant agent, has been demonstrated to have many cardioprotective effects. However, whether early administration of trimetazidine has an effect on diabetic cardiomyopathy and the mechanisms underlying the effect have not yet been elucidated.MethodsWe established a type 2 DCM rat model by high-fat diet and low-dose streptozotocin. Rats were separated into different groups: control, diabetes, and diabetes + trimetazidine (n = 6, each). Cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.ResultsRats with type 2 DCM showed severe insulin resistance, left ventricular dysfunction, increased cardiomyocyte apoptosis, and reduced cardiac autophagy. Collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) ratio were significantly higher in the diabetic group than the control group. We found that trimetazidine treatment ameliorated metabolic disturbance and insulin resistance, reduced cardiomyocyte apoptosis, and restored cardiac autophagy. CVF and PVCA/LA ratio were also lower in the diabetes + trimetazidine group than the diabetic group (CVF, 4.75 ± 0.52 % vs. 11.04 ± 1.67 %,p< 0.05; PVCA/LA, 8.37 ± 0.51 vs. 17.97 ± 2.66,p< 0.05). Furthermore, trimetazidine inhibited phosphorylation of ERK and P38 MAPK to reduce myocardial fibrosis. Inhibited phosphorylation of AMPK was restored and the interaction between Bcl-2 and Beclin1 was enhanced in diabetes + trimetazidine group, resulting in the initiation of autophagy and alleviation of apoptosis.ConclusionsEarly administration of trimetazidine could ameliorate diabetic cardiomyopathy by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. Therefore, trimetazidine may be a good choice in the prevention of diabetic cardiomyopathy if applied at the early stage of diabetes.