| First Author | Chen YH | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 105 |
| Pages | 1-11 | PubMed ID | 28214509 |
| Mgi Jnum | J:251081 | Mgi Id | MGI:6102624 |
| Doi | 10.1016/j.yjmcc.2017.02.002 | Citation | Chen YH, et al. (2017) Haplodeficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function. J Mol Cell Cardiol 105:1-11 |
| abstractText | 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-beta (transforming growth factor-beta)/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. |
