Chang-Yi Li1, Yi-He Chen, Qian Wang, Jian-Wen Hou, Hong Wang, Yue-Peng Wang, Yi-Gang Li. 1. aDepartment of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China *Yi-Gang Li and Yue-Peng Wang contributed equally to the writing of this article.
Abstract
BACKGROUND: Activin receptor-like kinase 4 (ALK4), a downstream receptor of transforming growth factor-β superfamily, is highly expressed in the mammal heart. Upregulated ALK4 expression and activated ALK4-small mother against decapentaplegic (Smad)2/3 signaling have been reported to play a pivotal role in tumorigenesis and in the development of systemic sclerosis. However, the role of ALK4-Smad2/3 pathway in the pathogenesis of cardiac hypertrophy and cardiac fibrosis remains unknown. METHODS AND RESULTS: In this study, the mice with heterozygous knocking out of ALK4 gene (ALK4) were generated and subjected to aortic banding for 4 weeks. We found that ALK4 expression was upregulated in aortic banding-induced model of cardiac hypertrophy and cardiac fibrosis in wild-type mice. Compared with the wild-type mice, ALK4mice demonstrated a similar extent of aortic banding-induced cardiac hypertrophy, but a significant suppression of cardiac fibrosis to 64.8% of the basal level, and a subsequent amelioration in the cardiac dysfunction (left ventricle ejection fraction: 59.0 ± 6.4 in wild-type mice vs. 75.6 ± 3.9% in ALK4 mice; left ventricle end-diastolic pressure: 16.6 ± 4.7 mmHg in wild-type mice vs. 6.6 ± 2.8 mmHg in ALK4 mice) associated with inhibition of cardiac fibroblast activation and cardiomyocyte apoptosis. In vitro, ALK4 haploinsufficiency blocked the cellular proliferation/differentiation and collagen production in cultured cardiac fibroblasts after angiotensin-II stimulation. Mechanistically, ALK4 haploinsufficiency resulted in the suppression of Smad2/3 activity. CONCLUSION: Our results demonstrate that ALK4 haploinsufficiency ameliorates cardiac fibrosis and dysfunction in a mouse pressure-overload model associated with inhibition of cardiac fibroblast activation and cardiomyocyte apoptosis through the suppression of Smad2/3 activity, and suggest that ALK4 is a novel therapeutic target in treating pressure overload-induced cardiac remodeling and heart failure.
BACKGROUND:Activin receptor-like kinase 4 (ALK4), a downstream receptor of transforming growth factor-β superfamily, is highly expressed in the mammal heart. Upregulated ALK4 expression and activated ALK4-small mother against decapentaplegic (Smad)2/3 signaling have been reported to play a pivotal role in tumorigenesis and in the development of systemic sclerosis. However, the role of ALK4-Smad2/3 pathway in the pathogenesis of cardiac hypertrophy and cardiac fibrosis remains unknown. METHODS AND RESULTS: In this study, the mice with heterozygous knocking out of ALK4 gene (ALK4) were generated and subjected to aortic banding for 4 weeks. We found that ALK4 expression was upregulated in aortic banding-induced model of cardiac hypertrophy and cardiac fibrosis in wild-type mice. Compared with the wild-type mice, ALK4mice demonstrated a similar extent of aortic banding-induced cardiac hypertrophy, but a significant suppression of cardiac fibrosis to 64.8% of the basal level, and a subsequent amelioration in the cardiac dysfunction (left ventricle ejection fraction: 59.0 ± 6.4 in wild-type mice vs. 75.6 ± 3.9% in ALK4mice; left ventricle end-diastolic pressure: 16.6 ± 4.7 mmHg in wild-type mice vs. 6.6 ± 2.8 mmHg in ALK4mice) associated with inhibition of cardiac fibroblast activation and cardiomyocyte apoptosis. In vitro, ALK4haploinsufficiency blocked the cellular proliferation/differentiation and collagen production in cultured cardiac fibroblasts after angiotensin-II stimulation. Mechanistically, ALK4haploinsufficiency resulted in the suppression of Smad2/3 activity. CONCLUSION: Our results demonstrate that ALK4haploinsufficiency ameliorates cardiac fibrosis and dysfunction in a mouse pressure-overload model associated with inhibition of cardiac fibroblast activation and cardiomyocyte apoptosis through the suppression of Smad2/3 activity, and suggest that ALK4 is a novel therapeutic target in treating pressure overload-induced cardiac remodeling and heart failure.
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312