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Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts.

ABSTRACT: Cardiac hypertrophy and fibrosis are the major causes of heart failure due to non-ischaemia heart disease. To date, no specific therapy exists for cardiac fibrosis due to the largely unknown mechanisms of disease and lack of applicable therapeutic targets. In this study, we aimed to explore the role and associated mechanism of peptidase inhibitor 16 (PI16) in cardiac fibrosis induced by angiotensin II. In cardiac fibroblasts (CFs), overexpressed PI16 significantly inhibited CF proliferation and the levels of fibrosis-associated proteins. Further analysis of epigenetic changes in CF revealed that overexpressed PI16 decreases the nuclear level of histone deacetylase 1 (HDAC1) after angiotensin II treatment, resulting in increased histone 3 acetylation in K18 and K27 lysine. However, overexpression of HDAC1 by an adenovirus vector in CFs reversed these changes. Echocardiography showed that PI16 transgenic (Tg) mice have smaller left ventricle mass than wild-type mice. Histological analysis data showed that PI16 Tg mice demonstrated smaller cardiomyocyte size and less collagen deposition than wild-type mice. The effects of PI16 on HDAC1 and histone 3 were also confirmed in PI16 Tg mice using immunostaining. Generally, PI16 is a HDAC1 regulator specifically in CFs, and PI16 overexpression prevents cardiac hypertrophy and fibrosis by inhibiting stress-induced CF activation.

SUBMITTER: Deng M

PROVIDER: S-EPMC7205788 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts.

Deng Mengqing M Yang Shuo S Ji Yue Y Lu Yan Y Qiu Ming M Sheng Yanhui Y Sun Wei W Kong Xiangqing X

Journal of cellular and molecular medicine 20200330 9

Cardiac hypertrophy and fibrosis are the major causes of heart failure due to non-ischaemia heart disease. To date, no specific therapy exists for cardiac fibrosis due to the largely unknown mechanisms of disease and lack of applicable therapeutic targets. In this study, we aimed to explore the role and associated mechanism of peptidase inhibitor 16 (PI16) in cardiac fibrosis induced by angiotensin II. In cardiac fibroblasts (CFs), overexpressed PI16 significantly inhibited CF proliferation and ...[more]

PMID: 32227584

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Project description:Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix in the myocardium with cardiac fibroblast activation, leading to chronic cardiac remodeling and dysfunction. However, little is known about metabolic alterations in fibroblasts during cardiac fibrosis, and there is a lack of pharmaceutical treatments that target metabolic dysregulation. Here, we provided evidence that fatty acid β-oxidation (FAO) dysregulation contributes to fibroblast activation and cardiac fibrosis. With transcriptome, metabolome, and functional assays, we demonstrated that FAO was downregulated during fibroblast activation and cardiac fibrosis, and that perturbation of FAO reversely affected the fibroblast-to-myofibroblast transition. The decrease in FAO may be attributed to reduced long-chain fatty acid (LCFA) uptake. Voltage-dependent anion channel 1 (VDAC1), the main gatekeeper of the outer mitochondrial membrane (OMM), serves as the transporter of LCFA into the mitochondria for further utilization and has been shown to be decreased in myofibroblasts. In vitro, the addition of exogenous VDAC1 was shown to ameliorate cardiac fibroblast activation initiated by transforming growth factor beta 1 (TGF-β1) stimuli, and silencing of VDAC1 displayed the opposite effect. A mechanistic study revealed that VDAC1 exerts a protective effect by regulating LCFA uptake into the mitochondria, which is impaired by an inhibitor of carnitine palmitoyltransferase 1A. In vivo, AAV9-mediated overexpression of VDAC1 in myofibroblasts significantly alleviated transverse aortic constriction (TAC)-induced cardiac fibrosis and rescued cardiac function in mice. Finally, we treated mice with the VDAC1-derived R-Tf-D-LP4 peptide, and the results showed that R-Tf-D-LP4 prevented TAC-induced cardiac fibrosis and dysfunction in mice. In conclusion, this study provides evidence that VDAC1 maintains FAO metabolism in cardiac fibroblasts to repress fibroblast activation and cardiac fibrosis and suggests that the VDAC1 peptide is a promising drug for rescuing fibroblast metabolism and repressing cardiac fibrosis.

Dataset Information

Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts.

Publications

Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts.

Similar Datasets

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