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.
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.
Matrix Biol. 2022 Sep;112:171-189. doi: 10.1016/j.matbio.2022.08.010. Epub 2022 Aug 27.
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.
心脏纤维化是多种心脏疾病的常见且不可逆转的病理特征。不受控制的心脏纤维化会导致适应性不良的心脏重构，并最终导致心力衰竭。然而，缺血性和非缺血性病理性心脏纤维化的分子决定因素在很大程度上仍然未知。在这里，我们研究了布鲁顿酪氨酸激酶（BTK）在各种病理条件下的小鼠心脏纤维化和重构中的作用。压力超负荷或心肌梗死（MI）后，BTK 在小鼠心肌中的表达增加。BTK 主要位于心肌中的心脏成纤维细胞中，TGF-β 处理后分离的心脏成纤维细胞中其表达也上调。BTK 的缺失或用第二代抑制剂阿卡鲁替尼进行药理学抑制减轻了心脏纤维化，保持了心脏功能，防止了不良的心脏重构，从而防止了压力超负荷或 MI 后小鼠发生心力衰竭。BTK 缺失或抑制剂治疗显著降低了分离的心脏成纤维细胞中促纤维化分子的表达，并抑制了成纤维细胞对各种病理应激的向肌成纤维细胞的转化。BTK 直接结合并在酪氨酸 182 处磷酸化 TGF-β 受体 Ⅰ（TβRⅠ），然后促进下游 SMAD 依赖性或非依赖性 TGF-β 信号的激活，导致成纤维细胞向促纤维化的肌成纤维细胞的过度转化和细胞外基质基因表达的过度。我们的发现揭示了 BTK 在压力超负荷和 MI 应激后心脏纤维化和功能障碍中的驱动作用，并强调了缺血性和非缺血性适应性不良心脏重构中的新发病机制，为抗纤维化治疗的发展提供了有希望的靶点。
