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.

Meteorin-like protein attenuates doxorubicin-induced cardiotoxicity via activating cAMP/PKA/SIRT1 pathway

“…Then the perfusate samples were centrifuged at 3000 rpm for a total of 45 min (Repeated for 3 times every 15 min). In addition, the adult mice cardiomyocytes (CMs) were isolated by the Langendorff perfusion system as our previously described and cultured in vitro for 4 h with the medium collected to detect METRNL secretion [ 31 ]. Cardiac endothelial cells (ECs) were isolated from adult mice using CD31 microbeads, while cardiac fibroblasts (CFs) were isolated using feeder removal microbeads with magnetic cell separation technology as our previously described [ 26 ].…”

HMGA1 Induction of miR-103/107 Forms a Negative Feedback Loop to Regulate Autophagy in MPTP Model of Parkinson’s Disease

“…Prior studies reveal that HMGA1 proteins regulate the transcription of genes primarily through binding to specific DNA sequences (AT-rich regions in the minor groove), altering chromatin structure, and recruiting other transcription factors (D’Angelo et al, 2017 ; Sgarra et al, 2018 ). They are considered to serve as critical genetic regulators and involve in diverse physiological and pathological progresses, including cell cycle regulation (Fedele et al, 2005 ), differentiation (Giannini et al, 2000 ), apoptosis (Pierantoni et al, 2007 ), cellular metabolism (Ha et al, 2012 ), mitochondrial regulation (Dement et al, 2007 ; Mao et al, 2009 ), and autophagic signaling pathway (Conte et al, 2017 ; Wu et al, 2020 ). Indeed, a large amount of evidence has demonstrated the pivotal role of HMGA1 in diverse, aggressive cancers and normal development (Schoenmakers et al, 1995 ; Wood et al, 2000 ; Reeves, 2001 ).…”

MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics

“…High-mobility group AT-hook 1 (HMGA1) is a key partaker in cardiovascular complications of diabetes, both at the vascular and the cardiac level [ 143 , 144 ]. HMGA1 expression is modulated by miRNAs known to be involved in cardiovascular disease, such as Let-7 and miR-26a [ 145 ].…”