Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice.
Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice.
复制标题
通过慢性二甲双胍治疗改善心脏功能与糖尿病OVE26小鼠的心脏自噬增强有关。
作者：
Xie Z;Lau K;Eby B;Lozano P;He C;Pennington B;Li H;Rathi S;Dong Y;Tian R;Kem D;Zou MH
自噬是清除聚集蛋白和受损细胞器的关键细胞系统。虽然自噬失调与心力衰竭的发生有关，但自噬在糖尿病性心肌病发生中的作用尚未得到研究。我们研究了二甲双胍慢性激活amp活化蛋白激酶（AMPK）是否能恢复OVE26糖尿病小鼠的心功能和心肌细胞自噬。用二甲双胍或对照药治疗OVE26小鼠和心脏特异性AMPK显性阴性转基因(DN)-AMPK糖尿病小鼠4个月，观察心脏自噬、心功能和心肌细胞凋亡情况。与对照组小鼠相比，糖尿病OVE26小鼠在体内和离体心脏中表现出AMPK活性的显著降低，同时心肌细胞自噬和心功能障碍也减少。此外，糖尿病OVE26小鼠心脏表现出分布混乱的线粒体聚集在组织不良的肌原纤维之间，多泛素化蛋白和细胞凋亡增加。通过过度表达心脏特异性DN-AMPK基因抑制AMPK可减少心肌细胞自噬，加重心功能障碍，并增加糖尿病小鼠的死亡率。最后，慢性二甲双胍治疗显著增强糖尿病OVE26小鼠的自噬活性和心脏功能，但在DN-AMPK糖尿病小鼠中没有。AMPK活性降低和随后的心脏自噬减少是糖尿病性心肌病发展的重要事件。二甲双胍慢性激活AMPK通过上调糖尿病OVE26小鼠的自噬活性来预防心肌病。因此，刺激AMPK可能是治疗糖尿病性心肌病的一种新方法。
Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice. OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice. Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy.