Exendin-4通过调控Sirt1/PGC1α延缓糖尿病小鼠心肌损伤

Exendin-4 alleviates diabetic cardiomyopathy in mice by regulating Sirt1/PGC1α

目的探讨exendin-4对2型糖尿病小鼠心肌的保护作用及其机制。方法将C57BL/6J小鼠分为正常组(Con)和糖尿病组(DM),Con组小鼠正常饮食,DM组小鼠利用高脂饮食联合链脲佐菌素进行造模,造模成功后的2型糖尿病小鼠分Exendin-4干预(DM+Ex-4)和糖尿病对照组(DM-Con)。DM+Ex-4组小鼠每天给予1 nmol/kg体质量的exendin-4腹腔注射,干预8周。DM-Con组给予等剂量的生理盐水腹腔注射。记录各组小鼠血糖、体质量等生理指标,RT-PCR检测心肌肥大、纤维化指标以及PGC1α、NRF、Cyto C等线粒体功能相关指标,Western blot检测氧化应激指标以及Sirt1/PGC1α通路表达情况,HE病理染色观察心肌结构变化。结果与Con组相比,DM-Con组的血糖、血脂均显著升高(P<0.001),心肌组织ANP、BNP、TGFβ1、Cyto C1、NOX1显著升高(P<0.05),而Sirt1、PGC1α、NRF、SOD1显著降低(P<0.05)。Exendin-4干预后,与DM-Con组相比,DM+Ex-4组小鼠血糖、血脂明显下降(P<0.05),心肌组织ANP、BNP、TGFβ1、Cyto C1、NOX1明显下降(P<0.05),Sirt1、PGC1α、NRF、SOD1表达升高(P<0.05)。结论 Exendin-4通过调控心肌组织Sirt1/PGC1α信号通路,改善线粒体功能,抑制氧化应激,从而缓解糖尿病小鼠心肌损伤。

Objective To investigate the protective effect of exendin-4 against diabetic cardiomyopathy in mice and explore the underlying mechanism. Methods C57 BL/6 J mice were randomly divided into normal control group with normal diet and diabetic group with high-fat diet for 4 weeks before streptozotocin injection. The successfully established diabetic mouse models were divided into diabetic group with exendin-4 treatment and diabetic control group for daily treatment with intraperitoneal injection of 1 nmol/kg exendin-4 and saline of equivalent volume for 8 weeks, respectively. The physiological parameters such as blood glucose and body weight were recorded. RT-PCR was used to examine the transcription levels of genes related with myocardial hypertrophy and fibrosis and the genes related with mitochondrial functions including PGC1α,NRF and Cyto C. The expressions of oxidative stress markers and Sirt1/PGC1 proteins were measured using Western blotting.and HE staining was used to observe the myocardial structural changes in the mice. Results Compared with the normal control mice, the mice in diabetic control group showed significantly increased blood glucose and blood lipid levels（P〈0.001）,which were obviously improved by Exendin-4 treatment. The expressions of ANP, BNP, TGFβ1, Cyto C1 and NOX1 were significantly increased（P〈0.05） while Sirt1, PGC1α, NRF and SOD1 expression were markedly decreased in the myocardial tissue of the diabetic mice（P〈0.05）. Exendin-4 treatment resulted in obviously reduced expressions of ANP, BNP, TGFβ1,Cyto C1 and NOX1（P〈0.05） and increased expressions of Sirt1, PGC1α, NRF and SOD1（P〈0.05） in the diabetic mice.Conclusions Exendin-4 protects against myocardial injury in diabetic mice by improving mitochondrial function and inhibiting oxidative stress through the Sirt1/PGC1α signaling pathway.