1. Partial inhibition of activin receptor-like kinase 4 attenuates pressure overload-induced cardiac fibrosis and improves cardiac function.
- Author
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Li CY, Chen YH, Wang Q, Hou JW, Wang H, Wang YP, and Li YG
- Subjects
- Activin Receptors, Type I genetics, Activin Receptors, Type I metabolism, Angiotensin II pharmacology, Animals, Aorta pathology, Apoptosis, Blood Pressure, Cardiomegaly metabolism, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Collagen biosynthesis, Disease Models, Animal, Fibroblasts drug effects, Fibroblasts physiology, Fibrosis, Haploinsufficiency, Heterozygote, Male, Mice, Myocytes, Cardiac physiology, Signal Transduction, Smad2 Protein metabolism, Smad3 Protein metabolism, Stroke Volume, Transforming Growth Factor beta metabolism, Up-Regulation, Ventricular Dysfunction, Left genetics, Ventricular Dysfunction, Left physiopathology, Activin Receptors, Type I antagonists & inhibitors, Cardiomegaly genetics, Cardiomegaly pathology, Myocardium pathology
- 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.
- Published
- 2016
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