title: Sirt3 deficiency exacerbates diabetic cardiac dysfunction: Role of Foxo3A-Parkin-mediated mitophagy.
abstract: Diabetic cardiomyopathy (DCM) is often associated with suppressed cardiac autophagy, mitochondrial structural and functional impairment. Sirtuin-3 (Sirt3) has been reported to play a crucial role in mitochondrial homeostasis and confers a protective role against the onset and development of DCM although the precise mechanism(s) remains elusive. Here we hypothesized that Sirt3 exerts cardioprotection against DCM by activating Parkin-mediated mitophagy, en route to preserved mitochondrial homeostasis and suppressed cardiomyocyte apoptosis. Adult male wild-type (WT) and Sirt3 knockout (Sirt3KO) mice were treated with streptozotocin (STZ) or vehicle for 3months prior to assessment of echocardiographic property, interstitial fibrosis, cardiomyocyte apoptosis, mitochondrial morphology, cardiac autophagy and cell signaling molecules. Our findings revealed that STZ-induced diabetes mellitus prompted cardiac dysfunction, interstitial fibrosis, cardiomyocyte apoptosis and mitochondrial injury, accompanied with suppressed autophagy and mitophagy, the effects of which were aggravated by Sirt3KO. To the contrary, Sirt3 overexpression in vitro activated autophagy and mitophagy, inhibited mitochondrial injury and cardiomyocyte apoptosis, the effects of which were attenuated by autophagy inhibition using 3-MA. Moreover, deacetylation of Foxo3A and expression of Parkin were decreased by Sirt3KO, while these effects were facilitated by Sirt3OE in diabetic and high glucose settings. Taken together, our data suggested that suppressed Sirt3-Foxo3A-Parkin signaling mediated downregulation of mitophagy may play a vital role in the development of diabetic cardiomyopathy. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure edited by Dr. Jun Ren & Yingmei Zhang.
authors: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, 306th Hospital of CPLA, Beijing 100101, China; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Wenjun
authors: W
authors: Yu
authors: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Beilei
authors: B
authors: Gao
authors: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Yuncheng Central Hospital, Yuncheng 044000, Shanxi Province, China.
authors: Na
authors: N
authors: Li
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; Department of ICU, 309th Hospital of CPLA, Beijing 100092, China.
authors: Jiaxing
authors: J
authors: Wang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Cuiting
authors: C
authors: Qiu
authors: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Guoyong
authors: G
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Min
authors: M
authors: Liu
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Rongqing
authors: R
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors: Congye
authors: C
authors: Li
authors: Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: jigang@fmmu.edu.cn.
authors: Gang
authors: G
authors: Ji
authors: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: zhangym197951@126.com.
authors: Yingmei
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000172:deficiency*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C525046:Sirt3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D056566:Sirtuin 3
keywords: Cardiac function; Foxo3A; Mitophagy; Parkin; Sirt3; Streptozotocin