Ji Lele, Liu Fengzhou, Jing Zhe, Huang Qichao, Zhao Ya, Cao Haiyan, Li Jun, Yin Chun, Xing Jinliang, Li Fei
State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Diabetes. 2017 Jun;66(6):1586-1600. doi: 10.2337/db16-1237. Epub 2017 Mar 14.
Diabetic cardiomyopathy is a major cause of mortality in patients with diabetes, but specific strategies for preventing or treating diabetic cardiomyopathy have not been clarified yet. MICU1 is a key regulator of mitochondrial Ca uptake, which plays important roles in regulating mitochondrial oxidative phosphorylation and redox balance. To date, however, the significance of MICU1 in diabetic hearts has not been investigated. Here, we demonstrate that MICU1 was downregulated in mouse hearts, which contributes to myocardial apoptosis in diabetes. Importantly, the reconstitution of MICU1 in diabetic hearts significantly inhibited the development of diabetic cardiomyopathy, as evidenced by enhanced cardiac function and reduced cardiac hypertrophy and myocardial fibrosis in mice. Moreover, our in vitro data show that the reconstitution of MICU1 inhibited the apoptosis of cardiomyocytes, induced by high glucose and high fat, through increasing mitochondrial Ca uptake and subsequently activating the antioxidant system. Finally, our results indicate that hyperglycemia and hyperlipidemia induced the downregulation of MICU1 by inhibiting Sp1 expression in diabetic cardiomyocytes. Collectively, our findings provide the first direct evidence that upregulated MICU1 preserves cardiac function in diabetic mice, suggesting that increasing the expression or activity of MICU1 may be a pharmacological approach to ameliorate cardiomyopathy in diabetes.
糖尿病性心肌病是糖尿病患者死亡的主要原因，但预防或治疗糖尿病性心肌病的具体策略尚未明确。线粒体钙摄取1（MICU1）是线粒体钙摄取的关键调节因子，在调节线粒体氧化磷酸化和氧化还原平衡中起重要作用。然而，迄今为止，MICU1在糖尿病心脏中的意义尚未得到研究。在此，我们证明MICU1在小鼠心脏中表达下调，这导致糖尿病心肌细胞凋亡。重要的是，在糖尿病心脏中重建MICU1可显著抑制糖尿病性心肌病的发展，小鼠心脏功能增强、心脏肥大减轻和心肌纤维化减少证明了这一点。此外，我们的体外数据表明，重建MICU1通过增加线粒体钙摄取并随后激活抗氧化系统，抑制了高糖和高脂诱导的心肌细胞凋亡。最后，我们的结果表明，高血糖和高血脂通过抑制糖尿病心肌细胞中Sp1的表达诱导MICU1下调。总的来说，我们的研究结果提供了首个直接证据，即上调MICU1可维持糖尿病小鼠的心脏功能，这表明增加MICU1的表达或活性可能是改善糖尿病心肌病的一种药理学方法。
