Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation

Dandan Wang; Xiaoyue Hu; Seung Hee Lee; Feng Chen; Kai Jiang; Zizhuo Tu; Zejian Liu; Jing Du; Li Wang; Chaoying Yin; Yu Liao; Hongcai Shang; Kathleen A Martin; Raimund I Herzog; Lawrence H Young; Li Qian; John Hwa; Yaozu Xiang

doi:10.1016/j.jacbts.2018.01.005

Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation

JACC Basic Transl Sci. 2018 May 16;3(3):350-362. doi: 10.1016/j.jacbts.2018.01.005. eCollection 2018 Jun.

Authors

Dandan Wang¹, Xiaoyue Hu², Seung Hee Lee², Feng Chen¹, Kai Jiang¹, Zizhuo Tu¹, Zejian Liu³, Jing Du², Li Wang⁴, Chaoying Yin⁴, Yu Liao⁵, Hongcai Shang⁶, Kathleen A Martin², Raimund I Herzog³, Lawrence H Young², Li Qian⁴, John Hwa², Yaozu Xiang¹

Affiliations

¹ Shanghai East Hospital, School of Life Sciences and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China.
² Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
³ Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
⁴ McAllister Heart Institute, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.
⁵ Department of Endocrinology and Metabolism, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁶ Key laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.

Abstract

Management for patients with diabetes experiencing myocardial infarction remains a challenge. Here the authors show that hyperglycemia- and hyperinsulinemia-induced microRNA-24 (miR-24) reduction and O-GlcNAcylation in the diabetic heart contribute to poor survival and increased infarct size in diabetic myocardial ischemia/reperfusion (I/R). In a mouse model of myocardial I/R, pharmacological or genetic overexpression of miR-24 in hearts significantly reduced myocardial infarct size. Experimental validation revealed that miR-24 targets multiple key proteins, including O-GlcNac transferase, ATG4A, and BIM, to coordinately protect the myocardium from I/R injury. These results establish miR-24 as a promising therapeutic candidate for diabetic I/R injury.

Keywords: ATG4A, autophagy-related gene 4a; BIM, Bcl-2-like protein 11; CVD, cardiovascular disease; DM, diabetes mellitus; I/R, ischemia/reperfusion; MI, myocardial infarction; O-GlcNAcylation; OGT, O-GlcNac transferase; hyperinsulinemia; infarct size; microRNA.

Abstract

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