VPO1 Promotes Programmed Necrosis of Cardiomyocytes in Rats with Chronic Heart Failure by Upregulating CYLD

Yinzhuang Zhang; Zhijie Shen; Zhuoni Mao; Dan Huang; Chengyu Lou; Li Fang

doi:10.31083/j.fbl2912425

Frontiers in Bioscience-Landmark (Dec 2024)

VPO1 Promotes Programmed Necrosis of Cardiomyocytes in Rats with Chronic Heart Failure by Upregulating CYLD

Yinzhuang Zhang,
Zhijie Shen,
Zhuoni Mao,
Dan Huang,
Chengyu Lou,
Li Fang

Affiliations

Yinzhuang Zhang: Department of Cardiovascular Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, 410008 Changsha, Hunan, China
Zhijie Shen: Department of Cardiovascular Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, 410008 Changsha, Hunan, China
Zhuoni Mao: Department of Cardiovascular Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, 410008 Changsha, Hunan, China
Dan Huang: Department of Cardiovascular Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, 410008 Changsha, Hunan, China
Chengyu Lou: Department of Cardiovascular Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, 410008 Changsha, Hunan, China
Li Fang: Department of Cardiovascular Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, 410008 Changsha, Hunan, China

DOI: https://doi.org/10.31083/j.fbl2912425
Journal volume & issue: Vol. 29, no. 12
p. 425

Abstract

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Background: Chronic heart failure (CHF) is a serious cardiovascular condition. Vascular peroxidase 1 (VPO1) is associated with various cardiovascular diseases, yet its role in CHF remains unclear. This research aims to explore the involvement of VPO1 in CHF. Methods: CHF was induced in rats using adriamycin, and the expression levels of VPO1 and cylindromatosis (CYLD) were assessed. In parallel, the effects of VPO1 on programmed necrosis in H9c2 cells were evaluated through cell viability assays, lactate dehydrogenase (LDH) level measurements, and analysis of receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein (RIPK1/RIPK3/MLKL) pathway-related proteins. The impact of CYLD on RIPK1 protein stability and ubiquitination was also investigated, along with the interaction between VPO1 and CYLD. Additionally, cardiac structure and function were assessed using echocardiography, Hematoxylin-eosin (HE) staining, Masson staining, and measurements of myocardial injury-related factors, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), Aspartate aminotransferase (AST), LDH, and creatine kinase-myocardial band (CK-MB). Results: VPO1 expression was upregulated in CHF rats and in H9c2 cells treated with adriamycin. In cellular experiments, VPO1 knockdown improved cell viability, inhibited necrosis and the expression of proteins associated with the RIPK1/RIPK3/MLKL pathway. Mechanistically, VPO1 promoted cardiomyocyte programmed necrosis by interacting with the deubiquitinating enzyme CYLD, which enhanced RIPK1 ubiquitination and degradation, leading to activation of the RIPK1/RIPK3/MLKL signaling pathway. At animal level, overexpression of CYLD counteracted the cardiac failure, cardiac hypertrophy, myocardial injury, myocardial fibrosis, and tissue necrosis caused by VPO1 knockdown. Conclusions: VPO1 exacerbates cardiomyocyte programmed necrosis in CHF rats by upregulating CYLD, which activates the RIPK1/RIPK3/MLKL signaling pathway. Thus, VPO1 may represent a potential therapeutic target for CHF.

Published in Frontiers in Bioscience-Landmark

ISSN: 2768-6701 (Print); 2768-6698 (Online)
Publisher: IMR Press
Country of publisher: Singapore
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry; Science: Biology (General)
Website: https://www.imrpress.com/journal/FBL

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