Partial inhibition of activin receptor-like kinase 4 attenuates pressure overload-induced cardiac fibrosis and improves cardiac function

作者：Li, Chang-Yi; Chen, Yi-He; Wang, Qian; Hou, Jian-Wen; Wang, Hong; Wang, Yue-Peng; Li, Yi-Gang^*

来源：Journal of Hypertension, 2016, 34(9): 1766-1777.

DOI：10.1097/HJH.0000000000001020

• activin receptor-like kinase 4
• cardiac hypertrophy
• heart failure
• myocardiac fibrosis
• smads

Background: Activin receptor-like kinase 4 (ALK4), a downstream receptor of transforming growth factor-beta superfamily, is highly expressed in the mammal heart. Upregulated ALK4 expression and activated ALK4-Smad2/3 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, ALK4(+/)-mice 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 dysleft ventricle ejection fraction: 59.0-6.4 in wild-type mice vs. 75.6-3.9% in ALK4(+/)-mice; left ventricle end-diastolic pressure: 16.6-4.7mmHg in wild-type mice vs. 6.6-2.8mmHg 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.

• 出版日期2016-9
• 单位上海交通大学