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

Qing-Qing Wu,Haiming Wu,Yuan Yuan,Qizhu Tang,Chen Liu,Mingxia Duan,Zhulan Cai,Qingwen Xie,Tongtong Hu

doi:10.1038/s41419-020-2316-4

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.

Highlights

Epidemiological evidence shows that diabetes mellitus (DM) is strongly associated with heart failure (HF)
HMGA1 expression pattern in Diabetic cardiomyopathy (DCM) hearts To explore whether the expression level of HMGA1 changes in the pathology of DCM, we first detected HMGA1 expression in DCM mouse hearts and highglucose (HG)-stimulated cardiomyocytes
HMGA1 was upregulated in DCM mouse hearts (Fig. 1a, b) as well as HG-stimulated cardiomyocytes (Fig. 1c, d)

Summary

Introduction

Epidemiological evidence shows that diabetes mellitus (DM) is strongly associated with heart failure (HF). The. Official journal of the Cell Death Differentiation Association. Wu et al Cell Death and Disease (2020)11:160. Studies have confirmed the crucial role of autophagy in the development of diabetic cardiomyopathy. In OVE26 mice (develop type 1 diabetic model within 24 h after birth because of beta cell‐specific damage due to a calmodulin transgene regulated by the insulin promoter) cardiac autophagy was inhibited[9]. Suppression of cardiac autophagy was discovered in STZ-induced diabetic mice[10,11]. In a high-fat diet-induced type 2 DCM mice model (a well-characterized model that results in hyperglycemia, hyperinsulinemia, insulin resistance, defective islet compensation, and impaired glucose tolerance), autophagic flux decreased in myocardial tissue[12]. Studies indicated that restoring cardiac autophagy protected against cardiac remodeling in DCM9,11. Regulating autophagy may be a beneficial target for treating DCM

Objectives

Methods

Results

Conclusion