Wang Qian, Yu Ying, Zhang Pengpai, Chen Yihe, Li Changyi, Chen Jie, Wang Yuepeng, Li Yigang
Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Basic Res Cardiol. 2017 Jul;112(4):47. doi: 10.1007/s00395-017-0634-1. Epub 2017 Jun 21.
Atrial fibrosis, the hallmark of structural remodeling associated with atrial fibrillation (AF), is characterized by abnormal proliferation of atrial fibroblasts and excessive deposition of extracellular matrix. Transforming growth factor-β1 (TGF-β1)/activin receptor-like kinase 5 (ALK5)/Smad2/3/4 pathway has been reported to be involved in the process. Recent studies have implicated both activin A and its specific downstream component activin receptor-like kinase 4 (ALK4) in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 haplodeficiency attenuated the pressure overload- and myocardial infarction-induced ventricular fibrosis. However, the role of activin A/ALK4 in the pathogenesis of atrial fibrosis and vulnerability to AF remains unknown. Our study provided experimental and clinical evidence for the involvement of activin A and ALK4 in the pathophysiology of atrial fibrosis and AF. Patients with AF had higher activin A and ALK4 expression in atriums as compared to individuals devoid of AF. After angiotensin-II (Ang-II) stimulation which mimicked atrial fibrosis progression, ALK4-deficient mice showed lower expression of ALK4 in atriums, reduced activation of atrial fibroblasts, blunted atrial enlargement and atrial fibrosis, and further reduced AF vulnerability upon right atrial electrophysiological studies as compared to wild-type littermates. Moreover, we found that apart from the well-known TGF-β1/ALK5 pathway, the activation of activin A/ALK4/smad2/3 pathway played an important role in the pathogenesis of Ang-II-mediated atrial fibrosis and inducibility of AF, suggesting that targeting ALK4 might be a potential therapy for atrial fibrosis and AF.
心房纤维化是与心房颤动（AF）相关的结构重塑的标志，其特征在于心房成纤维细胞异常增殖和细胞外基质过度沉积。据报道，转化生长因子-β1（TGF-β1）/激活素受体样激酶5（ALK5）/Smad2/3/4信号通路参与了这一过程。最近的研究表明，激活素A及其特定的下游成分激活素受体样激酶4（ALK4）均参与非心脏器官的纤维化刺激。我们最近报道，ALK4单倍体不足可减轻压力超负荷和心肌梗死诱导的心室纤维化。然而，激活素A/ALK4在心房纤维化发病机制和AF易感性中的作用仍不清楚。我们的研究为激活素A和ALK4参与心房纤维化和AF的病理生理学提供了实验和临床证据。与无AF的个体相比，AF患者心房中的激活素A和ALK4表达更高。在模拟心房纤维化进展的血管紧张素II（Ang-II）刺激后，与野生型同窝小鼠相比，ALK4缺陷小鼠心房中ALK4的表达较低，心房成纤维细胞的激活减少，心房扩大和心房纤维化减轻，并且在右心房电生理研究中AF易感性进一步降低。此外，我们发现，除了众所周知的TGF-β1/ALK5信号通路外，激活素A/ALK4/smad2/3信号通路的激活在Ang-II介导的心房纤维化发病机制和AF诱导中起重要作用，这表明靶向ALK4可能是治疗心房纤维化和AF的潜在方法。
