Section of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Diabetes. 2011 Jun;60(6):1770-8. doi: 10.2337/db10-0351. Epub 2011 May 11.
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.
自噬是一种重要的细胞系统，可用于清除聚集的蛋白质和受损的细胞器。尽管自噬失调与心力衰竭的发生有关，但自噬在糖尿病心肌病的发生中的作用尚未得到研究。我们研究了二甲双胍通过慢性激活 AMP 激活蛋白激酶（AMPK）是否可以恢复 OVE26 糖尿病小鼠的心脏功能和心肌自噬。
用二甲双胍或载体处理 OVE26 小鼠和心脏特异性 AMPK 显性负突变体（DN）-AMPK 糖尿病小鼠 4 个月，并监测心脏自噬、心脏功能和心肌细胞凋亡。
与对照组相比，糖尿病 OVE26 小鼠的 AMPK 活性显著降低，同时伴有体内和离体心脏心肌自噬减少和心脏功能障碍。此外，糖尿病 OVE26 小鼠心脏表现出线粒体杂乱分布的聚集，肌原纤维之间排列紊乱，多聚泛素化蛋白和凋亡增加。通过心脏特异性 DN-AMPK 基因的过表达抑制 AMPK 减少了心肌自噬，加剧了糖尿病小鼠的心脏功能障碍，并增加了死亡率。最后，慢性二甲双胍治疗可显著增强糖尿病 OVE26 小鼠的自噬活性并保留心脏功能，但对 DN-AMPK 糖尿病小鼠则没有作用。
AMPK 活性降低和随后的心脏自噬减少是糖尿病心肌病发生的重要事件。二甲双胍通过慢性激活 AMPK 可通过上调糖尿病 OVE26 小鼠的自噬活性来预防心肌病。因此，刺激 AMPK 可能是治疗糖尿病心肌病的一种新方法。
