Kanamori Hiromitsu, Takemura Genzou, Goto Kazuko, Tsujimoto Akiko, Mikami Atsushi, Ogino Atsushi, Watanabe Takatomo, Morishita Kentaro, Okada Hideshi, Kawasaki Masanori, Seishima Mitsuru, Minatoguchi Shinya
a Department of Cardiology; Gifu University Graduate School of Medicine ; Gifu , Japan.
Autophagy. 2015;11(7):1146-60. doi: 10.1080/15548627.2015.1051295.
Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electron-microscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/+ mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.
目前对于自噬与糖尿病性心肌病之间的关联了解甚少。1型和2型糖尿病中心脏自噬可能存在的区别特征也尚不明确。在链脲佐菌素诱导的1型糖尿病小鼠心脏中，舒张功能受损，尽管自噬活性显著增加，这可通过微管相关蛋白1轻链3/LC3及LC3-II/-I比值、SQSTM1/p62（聚集体蛋白1）和CTSD（组织蛋白酶D）的增加以及电镜检测到的自噬泡和溶酶体数量增多得以证明。1型糖尿病心脏中AMP激活的蛋白激酶（AMPK）被激活且ATP含量降低。用自噬抑制剂氯喹治疗会使1型糖尿病的心脏功能恶化。此外，db/db 2型糖尿病模型小鼠的心脏舒张功能比db/+对照小鼠的心脏更差。然而，尽管有大量自噬泡，但LC3-II、SQSTM1和磷酸化的MTOR（雷帕霉素作用靶点）水平升高，而CTSD降低，超微结构检测到的溶酶体很少。2型糖尿病心脏中AMPK活性受到抑制且ATP含量降低。这些发现表明2型糖尿病心脏在最终消化步骤的自噬过程受到抑制。自噬增强剂白藜芦醇可减轻舒张功能障碍，而氯喹在2型糖尿病心脏中则产生相反作用。1型糖尿病中心脏自噬增强，但2型糖尿病中自噬受到抑制。这种差异为糖尿病性心肌病的病理生理学提供了重要见解，这对于新治疗策略的开发至关重要。
