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Exp Clin Endocrinol Diabetes 2022; 130(10): 660-670
DOI: 10.1055/a-1780-8768
Article

HDAC1 Promotes Myocardial Fibrosis in Diabetic Cardiomyopathy by Inhibiting BMP-7 Transcription Through Histone Deacetylation

Chun Ouyang
1   Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen City 518036, Guangdong Province, P.R. China
,
Lei Huang
1   Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen City 518036, Guangdong Province, P.R. China
,
Xiaoqiang Ye
1   Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen City 518036, Guangdong Province, P.R. China
,
Mingming Ren
1   Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen City 518036, Guangdong Province, P.R. China
,
Zhen Han
1   Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen City 518036, Guangdong Province, P.R. China
› Author Affiliations Funding This research was supported by funds from the Shenzhen Scientific Innovation Committee for the research on Diagnosis and treatment of cardiovascular diseases based on glycolysis (JCYJ20170412150405310) and the Shenzhen Municipal Health and Family Planning Commission for the Study on the clinical application of 3D printing and rapid prototyping technology in the treatment of Complex abdominal aortic aneurysm (SZFZ2018071).
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Abstract

Objective Diabetic cardiomyopathy (DCM) constitutes a primary cause of mortality in diabetic patients. Histone deacetylase (HDAC) inhibition can alleviate diabetes-associated myocardial injury. This study investigated the mechanism of HDAC1 on myocardial fibrosis (MF) in DCM.

Methods A murine model of DCM was established by a high-fat diet and streptozotocin injection. The bodyweight, blood glucose, serum insulin, and cardiac function of mice were analyzed. Lentivirus-packaged sh-HDAC1 was injected into DCM mice and high glucose (HG)-induced cardiac fibroblasts (CFs). The pathological structure of the myocardium and the level of myocardial fibrosis were observed by histological staining. HDAC1 expression in mouse myocardial tissues and CFs was determined. Collagen I, collagen III, alpha-smooth muscle actin (α-SMA), and vimentin levels in CFs were detected, and CF proliferation was tested. HDAC activity and histone acetylation levels in tissues and cells were measured. Bone morphogenetic protein-7 (BMP-7) expression in myocardial tissues and CFs was determined. Functional rescue experiments were conducted to confirm the effects of histone acetylation and BMP-7 on myocardial fibrosis.

Results DCM mice showed decreased bodyweight, elevated blood glucose and serum insulin, and cardiac dysfunction. Elevated HDAC1 and reduced BMP-7 expressions were detected in DCM mice and HG-induced CFs. HDAC1 repressed BMP-7 transcription through deacetylation. HDAC1 silencing alleviated MF, reduced CF proliferation and decreased collagen I, -III, α-SMA, and vimentin levels. However, reducing histone acetylation level or BMP-7 downregulation reversed the effects of HDAC1 silencing on CF fibrosis.

Conclusion HDAC1 repressed BMP-7 transcription by enhancing histone deacetylation, thereby promoting MF and aggravating DCM.

Key words

HDAC1 - diabetic cardiomyopathy - myocardial fibrosis - histone acetylation - BMP-7 - cardiac fibroblasts


Publication History

Received: 22 September 2021
Received: 10 January 2022

Accepted: 17 February 2022

Article published online:
27 June 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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