尿石素A通过促进线粒体自噬保护糖尿病小鼠心脏损伤的作用研究

Urolithin A prevents occurrence of diabetic cardiomyopathy via activating mitophagy

目的探讨尿石素A(urolithin A,UA)对糖尿病小鼠心脏的保护作用及其机制。方法健康♂C57BL/6小鼠连续6 d腹腔注射链脲佐菌素诱导糖尿病模型,UA连续灌胃11周,并定期检测体质量和随机血糖。在第17周行超声检测心功能,Western blot法测定心肌组织内间质胶原蛋白的变化。高糖33.3 mmol·L^-1刺激心肌成纤维细胞,并给予UA进行处理。荧光探针和Western blot法检测线粒体自噬及极性受损线粒体含量的变化情况。结果UA对小鼠的体质量、血糖、糖耐量、心功能均无明显影响。但能明显改善糖尿病小鼠心脏舒张功能障碍、减少心肌组织内FN和CollagenⅠ蛋白的表达。UA可激活心肌成纤维细胞内被高糖抑制的线粒体自噬。同时UA减少了极性受损线粒体的含量。UA的保护作用被线粒体自噬抑制剂Mdivi-1逆转。结论UA通过诱导细胞内的线粒体自噬,发挥了改善糖尿病小鼠心脏损伤的作用。

Aim To investigate the protective effect of urolithin A(UA)on diabetic cardiomyopathy and its possible mechanism.Methods Healthy male C57BL/6 mice received intraperitoneal injection of streptozotocin to induce the model of diabetes mellitus.UA was administered for 11 weeks,and body weight and random blood glucose were measured every other week.On 17th week,mice were sacrificed after the measurement of cardiac function and oral glucose tolerance.And the protein expressions of fibronectin(FN)and CollagenⅠin heart tissues were detected by Western blot.In vitro,the cardiac fibroblasts were stimulated by 33.3 mmol·L^-1 of glucose and treated with UA.JC-1 staining and immunoblots were performed to evaluate the contents of depolarized mitochondrial and the activity of mitophagy.Results UA did not alter body weight,blood glucose,and cardiac function in normal mice.However,UA improved cardiac diastolic dysfunction and alleviated the decrease of ventricular thickness in diabetic mice.UA also reduced cardiac expressions of FN and CollagenⅠ.In vitro,UA up-regulated the mitophagy which was inhibited by high glucose and reduced the contents of depolarized mitochondrial in cardiac fibroblasts.While Mdivi-1,a mitophagy inhibitor,significantly abrogated the effect of UA in eliminating depolarized mitochondrial.Conclusion UA protects the cardiac injury in diabetic mice through mitophagy activation.