Abstract
Phenotype switching of cardiac fibroblasts into myofibroblasts plays important role in cardiac fibrosis following myocardial infarction (MI). Cellular repressor of E1A-stimulated genes (CREG) protects against vascular and cardiac remodeling induced by angiotensin-II. However, the effects and mechanisms of CREG on phenotype switching of cardiac fibroblasts after MI are unknown. This study aimed to investigate the role of CREG on the phenotype switching of cardiac fibroblasts following MI and its mechanism. Our findings demonstrated that, compared with littermate control mice, cardiac function was deteriorated in CREG+/− mice on day 14 post-MI. Fibrosis size, αSMA, and collagen-1 expressions were increased in the border regions of CREG+/− mice on day 14 post-MI. Conversely, exogenous CREG protein significantly improved cardiac function, inhibited fibrosis, and reduced the expressions of αSMA and collagen-1 in the border regions of C57BL/6J mice on day 14. In vitro, CREG recombinant protein inhibited αSMA and collagen-1 expression and blocked the hypoxia-induced proliferation and migration of cardiac fibroblasts, which was mediated through the inhibition of cell division control protein 42 (CDC42) expression. Our findings could help in establishing new strategies based on the clarification of the role of the key molecule CREG in phenotype switching of cardiac fibroblasts following MI.
Highlights
Myocardial infraction (MI) is a major public health problem[1], and its mortality rate is decreasing with improved treatment strategies
Decreased Cellular repressor of E1A-stimulated genes (CREG) expression was associated with cardiac myofibroblast activation in the myocardium of C57BL/6J mice following MI
CREG deficiency aggravated myocardial fibrosis after MI We investigated whether the deteriorated cardiac function in CREG+/− mice was due, in part, to remodeling of the left ventricle by measuring the ratio of heart weightto-tibial length (HW/TL) and the ratio of heart length-totibial length (HL/TL)
Summary
Myocardial infraction (MI) is a major public health problem[1], and its mortality rate is decreasing with improved treatment strategies. MI-related heart failure remains a major problem without established targeted therapies. Post-MI cardiac remodeling results from several changes in the shape and function of the left ventricle, which lead to heart failure secondary to pathological changes of cardiac fibrosis[1,2,3]. Due to pathological stimuli, such as hypoxia, cardiac fibroblasts are activated and transformed into cardiac myofibroblasts[4], MI could provide new strategies for the prevention and treatment of heart failure following MI. Studies have indicated that CREG is an important myocardial protective factor[15,16,17]. CREG could promote cardiomyogenic differentiation by interacting with Sec[814]
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