title: MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca2+-Dependent Antioxidant Response.
abstract: 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 Ca2+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 indb/dbmouse 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 indb/dbmice. 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 Ca2+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 diabeticdb/dbmice, suggesting that increasing the expression or activity of MICU1 may be a pharmacological approach to ameliorate cardiomyopathy in diabetes.
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Fengzhou
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Cardiology, General Hospital of Lanzhou Military Area Command, Lanzhou, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China xingjinliang@163.com lifei2288@hotmail.com.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China xingjinliang@163.com lifei2288@hotmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D004452:Echocardiography; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002135:Calcium-Binding Proteins; C000610715:MICU1 protein, mouse; C000622000:MICU1 protein, rat; D033681:Mitochondrial Membrane Transport Proteins; D017382:Reactive Oxygen Species; D009243:NAD; D009249:NADP; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide