1. Academic Validation
  2. Loss of BTK ameliorates the pathological cardiac fibrosis and dysfunction

Loss of BTK ameliorates the pathological cardiac fibrosis and dysfunction

  • Matrix Biol. 2022 Sep;112:171-189. doi: 10.1016/j.matbio.2022.08.010.
Bo Wang 1 Yong Tan 2 Wenhui Zhou 2 Jing Yang 3 Yuyu Jiang 4 Xingguang Liu 5 Zhenzhen Zhan 6
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 2 Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 3 Department of Cardiology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui hospital, Fudan University, Shanghai 200031, China.
  • 4 Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China.
  • 5 Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China. Electronic address: liuxg@immunol.org.
  • 6 Department of Liver Surgery, Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: zhanzz@tongji.edu.cn.
Abstract

Cardiac fibrosis is a common irreversible pathological feature of diverse heart disorders. Uncontrolled cardiac fibrosis contributes to maladaptive cardiac remodeling and eventually heart failure. However, the molecular determinants of ischemic and non-ischemic pathological cardiac fibrosis remain largely unknown. Here, we investigated the role of Bruton's tyrosine kinase (Btk) in cardiac fibrosis and remodeling of mice under various pathological conditions. Btk expression was increased in myocardium of mice after pressure overload or myocardial infarction (MI). Btk was mainly located in cardiac fibroblasts of myocardium, and its expression in isolated cardiac fibroblasts was also upregulated following TGF-β treatment. The deficiency or pharmacological inhibition of Btk with the second-generation inhibitor Acalabrutinib attenuated cardiac fibrosis, preserved cardiac function and prevented adverse cardiac remodeling, which protected against heart failure in mice following pressure overload or MI. Btk deficiency or inhibitor treatment significantly decreased the expression of pro-fibrotic molecules in isolated cardiac fibroblasts and inhibited the transition of fibroblasts to myofibroblasts in response to diverse pathological stresses. Btk directly bound and phosphorylated TGF-β Receptor Ⅰ (TβRⅠ) at tyrosine 182, and then promoted the activation of downstream SMAD-dependent or -independent TGF-β signaling, leading to the enhanced transition of fibroblasts to pro-fibrotic myofibroblasts and the excessive extracellular matrix gene expression. Our finding uncovers a driving role of Btk in cardiac fibrosis and dysfunction following pressure overload and MI stress, and highlights novel pathogenic mechanisms in ischemic and non-ischemic maladaptive cardiac remodeling, which presents as a promising target for the development of anti-fibrotic therapy.

Keywords

Bruton's tyrosine kinase; Cardiac fibroblasts; Cardiac fibrosis; Heart failure; TGF-β receptor I.

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