title: Partial inhibition of activin receptor-like kinase 4 attenuates pressure overload-induced cardiac fibrosis and improves cardiac function.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Chang-Yi
authors.initials: CY
authors.lastname: Li
authors.forename: Yi-He
authors.initials: YH
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Hou
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Yue-Peng
authors.initials: YP
authors.lastname: Wang
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Li
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D001794:Blood Pressure; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005355:Fibrosis; D057895:Haploinsufficiency; D006579:Heterozygote; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013318:Stroke Volume; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D003094:Collagen; D030201:Activin Receptors, Type I; C498933:Acvr1b protein, mouse