PMID- 32123163 OWN - NLM STAT- MEDLINE DCOM- 20210408 LR - 20210408 IS - 2041-4889 (Electronic) VI - 11 IP - 3 DP - 2020 Mar 2 TI - High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition. PG - 160 LID - 10.1038/s41419-020-2316-4 [doi] LID - 160 AB - High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of biological processes. However, its effect on cardiac remodeling (refer to cardiac inflammation, apoptosis and dysfunction) in diabetic cardiomyopathy remains largely indistinct. In this study, we found that HMGA1 was upregulated in diabetic mouse hearts and high-glucose-stimulated cardiomyocytes. Overexpression of HMGA1 accelerated high-glucose-induced cardiomyocyte inflammation and apoptosis, while HMGA1 knockdown relieved inflammation and apoptosis in cardiomyocytes in response to high glucose. Overexpression of HMGA1 in mice heart by adeno-associated virus 9 (AAV9) delivery system deteriorated the inflammatory response, increased apoptosis and accelerated cardiac dysfunction in streptozotocin-induced diabetic mouse model. Knockdown of HMGA1 by AAV9-shHMGA1 in vivo ameliorated cardiac remodeling in diabetic mice. Mechanistically, we found that HMGA1 inhibited the formation rather than the degradation of autophagy by regulating P27/CDK2/mTOR signaling. CDK2 knockdown or P27 overexpression blurred HMGA1 overexpression-induced deteriorating effects in vitro. P27 overexpression in mice heart counteracted HMGA1 overexpression-induced increased cardiac remodeling in diabetic mice. The luciferase reporter experiment confirmed that the regulatory effect of HMGA1 on P27 was mediated by miR-222. In addition, a miR-222 antagomir counteracted HMGA1 overexpression-induced deteriorating effects in vitro. Taken together, our data indicate that HMGA1 aggravates diabetic cardiomyopathy by directly regulating miR-222 promoter activity, which inhibits P27/mTOR-induced autophagy. FAU - Wu, Qing-Qing AU - Wu QQ AUID- ORCID: 0000-0002-7475-5014 AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Liu, Chen AU - Liu C AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Cai, Zhulan AU - Cai Z AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Xie, Qingwen AU - Xie Q AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Hu, Tongtong AU - Hu T AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Duan, Mingxia AU - Duan M AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Wu, Haiming AU - Wu H AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. FAU - Yuan, Yuan AU - Yuan Y AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. whuyuanyuan@whu.edu.cn. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. whuyuanyuan@whu.edu.cn. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. whuyuanyuan@whu.edu.cn. FAU - Tang, Qizhu AU - Tang Q AD - Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China. qztang@whu.edu.cn. AD - Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, P. R. China. qztang@whu.edu.cn. AD - Hubei Key Laboratory of Cardiology, Wuhan, 430060, P. R. China. qztang@whu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200302 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (MicroRNAs) RN - 124544-67-8 (HMGA1a Protein) RN - 5W494URQ81 (Streptozocin) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects/*physiology MH - Diabetes Mellitus, Experimental/complications/*metabolism MH - Diabetic Cardiomyopathies/complications/*metabolism MH - HMGA1a Protein/genetics/*metabolism MH - Male MH - Mice, Inbred C57BL MH - MicroRNAs/metabolism MH - Myocytes, Cardiac/*metabolism MH - Streptozocin PMC - PMC7052237 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/03/04 06:00 MHDA- 2021/04/10 06:00 PMCR- 2020/03/02 CRDT- 2020/03/04 06:00 PHST- 2019/07/13 00:00 [received] PHST- 2020/01/09 00:00 [accepted] PHST- 2020/01/09 00:00 [revised] PHST- 2020/03/04 06:00 [entrez] PHST- 2020/03/04 06:00 [pubmed] PHST- 2021/04/10 06:00 [medline] PHST- 2020/03/02 00:00 [pmc-release] AID - 10.1038/s41419-020-2316-4 [pii] AID - 2316 [pii] AID - 10.1038/s41419-020-2316-4 [doi] PST - epublish SO - Cell Death Dis. 2020 Mar 2;11(3):160. doi: 10.1038/s41419-020-2316-4.