title: Haplodeficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function.
abstract: Cardiac fibrosis (CF), a repairing process following myocardial infarction (MI), is characterized by abnormal proliferation of cardiac fibroblasts and excessive deposition of extracellular matrix (ECM) resulting in inevitable resultant heart failure. TGF-β (transforming growth factor-β)/ALK5 (Activin receptor-like kinase 5)/Smad2/3/4 pathways have been reported to be involved in the process. Recent studies have implicated both activin and its specific downstream component ALK4 in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 is upregulated in the pressure-overloaded heart and its partial inhibition attenuated the pressure overload-induced CF and cardiac dysfunction. However, the role of ALK4 in the pathogenesis of MI-induced CF, which is usually more severe than that induced by pressure-overload, remains unknown. Here we report: 1) In a wild-type mouse model of MI, ALK4 upregulation was restricted in the fibroblasts of the infarct border zone; 2) In contrast, ALK4+/-mice with a haplodeficiency of ALK4 gene, showed a significantly attenuated CF in the border zone, with a smaller scar size, a preserved cardiac function and an improved survival rate post-MI; 3) Similarly to pressure-overloaded heart, these beneficial effects might be through a partial inactivation of the Smad3/4 pathway but not MAPK cascades; 4) The apoptotic rate of the cardiomyocytes were indistinguishable in the border zone of the wild-type control and ALK4+/-mice; 5) Cardiac fibroblasts isolated from ALK4+/-mice showed reduced migration, proliferation and ECM synthesis in response to hypoxia. These results indicate that partial inhibition of ALK4 may reduce MI-induced CF, suggesting ALK4 as a novel target for inhibition of unfavorable CF and for preservation of LV systolic function induced by not only pressure-overload but also MI.
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Yi-He
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Chang-Yi
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Hou
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China. Electronic address: ypwang555@aliyun.com.
authors.forename: Yue-Peng
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China. Electronic address: drliyigang@outlook.com.
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Li
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004452:Echocardiography; D005109:Extracellular Matrix; D005355:Fibrosis; D005786:Gene Expression Regulation; D005838:Genotype; D057895:Haploinsufficiency; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D009203:Myocardial Infarction / Q000209:etiology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D058628:Myofibroblasts / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D016276:Ventricular Function
chemical_list: D051900:Smad3 Protein; D051901:Smad4 Protein; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; C498933:Acvr1b protein, mouse
keywords: Activin receptor-like kinase 4; Cardiac fibrosis; MAPK; Myocardial infarction; Smads