High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition.

Abstract

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.

• Authors: Qing-Qing Wu, Chen Liu, Zhulan Cai, Qingwen Xie, Tongtong Hu, Mingxia Duan, Haiming Wu, Yuan Yuan, Qizhu Tang
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 3 Pg. 160 (03 02 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32123163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MicroRNAs
• HMGA1a Protein
• Streptozocin

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects, physiology)
• Diabetes Mellitus, Experimental (complications, metabolism)
• Diabetic Cardiomyopathies (complications, metabolism)
• HMGA1a Protein (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Myocytes, Cardiac (metabolism)
• Streptozocin