2. Academic Validation
  3. HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis

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

  • J Adv Res. 2024 Jan 12:S2090-1232(24)00025-0. doi: 10.1016/j.jare.2024.01.012.
Qian Mao 1,  Xiaojin Zhang 2,  Jinna Yang 2,  Qiuyue Kong 1,  Hao Cheng 3,  Wansu Yu 2,  Xiaofei Cao 1,  Yuehua Li 4,  Chuanfu Li 5,  Li Liu 6,  Zhengnian Ding 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 2 Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 3 Department of Anesthesiology, the First Affiliated Hospital with Wannan Medical College, Wuhu, China.
  • 4 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, China.
  • 5 Departments of Surgery, East Tennessee State University, Johnson City, TN 37614.
  • 6 Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Anesthesiology, the First Affiliated Hospital with Wannan Medical College, Wuhu, China.
  • 7 Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: zhengnianding@njmu.edu.cn.
PMID: 38219869 DOI: 10.1016/j.jare.2024.01.012
Abstract

Introduction: 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.

Objectives: This study investigated the role of Heat shock protein 12A (HSPA12A), an atypical member of the HSP70 family, in CF activation and MI-induced cardiac fibrosis.

Methods: 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.

Results: 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.

Conclusion: 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 strategy for the management of cardiac fibrosis in patients.

Keywords

Cardiac fibroblast activation; Cardiac fibrosis; Glycolysis; HSPA12A; USP10; p53.

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