| First Author | Li CY | Year | 2016 |
| Journal | J Hypertens | Volume | 34 |
| Issue | 9 | Pages | 1766-77 |
| PubMed ID | 27379535 | Mgi Jnum | J:280078 |
| Mgi Id | MGI:6367506 | Doi | 10.1097/HJH.0000000000001020 |
| Citation | Li CY, et al. (2016) Partial inhibition of activin receptor-like kinase 4 attenuates pressure overload-induced cardiac fibrosis and improves cardiac function. J Hypertens 34(9):1766-77 |
| abstractText | 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-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. |
