Dataset Information

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.

SUBMITTER: Wu QQ

PROVIDER: S-EPMC7052237 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wu Qing-Qing QQ Liu Chen C Cai Zhulan Z Xie Qingwen Q Hu Tongtong T Duan Mingxia M Wu Haiming H Yuan Yuan Y Tang Qizhu Q

Cell death & disease 20200302 3

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 inflamma ...[more]

PMID: 32123163

Similar Datasets

Project description:Aims: We previously found that complement components are upregulated in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and inhibiting the complement receptor C5aR reduces disease severity in desmin knockout (Des-/- ) mice, a model for ARVC. Here, we examined the mechanism underlying complement activation in ARVC, revealing a potential new therapeutic target. Methods: First, immunostaining, RT-PCR and western blot were used to detect the expression levels of complement and coagulation factors. Second, we knocked out the central complement component C3 in Des-/- mice (ARVC model) by crossing Des-/- mice with C3-/- mice to explore whether complement system activation occurs independently of the conventional pathway. Then, we evaluated whether a targeted intervention to coagulation system is effective to reduce myocardium injury. Finally, the plasma sC5b9 level was assessed to investigate the role in predicting adverse cardiac events in the ARVC cohort. Results: The complement system is activated in the myocardium in ARVC. Autoantibodies against myocardial proteins provided a possible mechanism underlying. Moreover, we found increased levels of myocardial C5 and the serum C5a in Des-/-C3-/- mice compared to wild-type mice, indicating that C5 is activated independently from the conventional pathway, presumably via the coagulation system. Crosstalk between the complement and coagulation systems exacerbated the myocardial injury in ARVC mice, and this injury was reduced by using the thrombin inhibitor lepirudin. In addition, we found significantly elevated plasma levels of sC5b9 and thrombin in patients, and this increase was correlated with all-cause mortality. Conclusions: These results suggest that crosstalk between the coagulation and complement systems plays a pathogenic role in cardiac dysfunction in ARVC. Thus, understanding this crosstalk may have important clinical implications with respect to diagnosing and treating ARVC.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets