HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis

• Published in: Journal of advanced research 2025-01, Vol.67, p.217-229
• Main Authors: Mao, Qian, Zhang, Xiaojin, Yang, Jinna, Kong, Qiuyue, Cheng, Hao, Yu, Wansu, Cao, Xiaofei, Li, Yuehua, Li, Chuanfu, Liu, Li, Ding, Zhengnian
• Format: Article
• Language: English
• Subjects: Animals; Cardiac fibroblast activation; Cardiac fibrosis; Fibroblasts - metabolism; Fibrosis - metabolism; Glycolysis; HSP70 Heat-Shock Proteins - metabolism; HSPA12A; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction - metabolism; Myocardium - metabolism; Myocardium - pathology; Myofibroblasts - metabolism; P53; Tumor Suppressor Protein p53 - metabolism; USP10
• ISSN: 2090-1232; 2090-1224; 2090-1224
• DOI: 10.1016/j.jare.2024.01.012

[Display omitted] •HSPA12A expression was decreased during CF activation.•Ablation of HSPA12A in mice aggravated injury-induced cardiac fibrosis.•HSPA12A was required for suppressing CF activation, and this action of HSPA12A was achieved by inhibiting glycolysis via increasing p53 protein stability.•HSPA12A acted as a scaffolding protein to binding both p53 and USP10.•USP10 mediated the HSPA12A-increased p53 protein stability. Cardiac fibrosis is the main driver for adverse remodeling and progressive functional decline in nearly all types of heart disease including myocardial infarction (MI). The activation of cardiac fibroblasts (CF) into myofibroblasts is responsible for cardiac fibrosis. Unfortunately, no ideal approach for controlling CF activation currently exists. This study investigated the role of Heat shock protein A12A (HSPA12A), an atypical member of the HSP70 family, in CF activation and MI-induced cardiac fibrosis. Primary CF and Hspa12a knockout mice were used in the experiments. CF activation was indicated by the upregulation of myofibroblast characters including alpha-Smooth muscle actin (αSMA), Collagen, and Fibronectin. Cardiac fibrosis was illustrated by Masson’s trichrome and picrosirius staining. Cardiac function was examined using echocardiography. Glycolytic activity was indicated by levels of extracellular lactate and the related protein expression. Protein stability was examined following cycloheximide and MG132 treatment. Protein-protein interaction was examined by immunoprecipitation-immunoblotting analysis. HSPA12A displayed a high expression level in quiescent CF but showed a decreased expression in activated CF, while ablation of HSPA12A in mice promoted CF activation and cardiac fibrosis following MI. HSPA12A overexpression inhibited the activation of primary CF through inhibiting glycolysis, while HSPA12A knockdown showed the opposite effects. Moreover, HSPA12A upregulated the protein expression of transcription factor p53, by which mediated the HSPA12A-induced inhibition of glycolysis and CF activation. Mechanistically, this action of HSPA12A was achieved by acting as a scaffolding protein to bind p53 and ubiquitin specific protease 10 (USP10), thereby promoting the USP10-mediated p53 protein stability and the p53-medicated glycolysis inhibition. The present study provided clear evidence that HSPA12A is a novel endogenous inhibitor of CF activation and cardiac fibrosis. Targeting HSPA12A in CF could represent a promising st