Abstract
The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.
Highlights
Cardiac fibrosis characterized by excessive synthesis or diminished degradation of extracellular matrix (ECM) proteins is a hallmark of most types of heart disease and contributes to the progression of heart failure [1]
insulin-like growth factor 1 receptor (IGF-1R) expression patterns in mouse hearts and generation of CFIGF1RKO mice Firstly, we examined the levels of Insulin-like growth factor (IGF)-1R in cardiac fibroblasts compared with cardiomyocytes isolated from mouse hearts using Langendorff perfusion
IGF-1 secretion was significantly increased in fibroblasts isolated from angiotensin II (AngII)/PE-infused mice compared with those isolated from vehicle-infused mice
Summary
Cardiac fibrosis characterized by excessive synthesis or diminished degradation of extracellular matrix (ECM) proteins is a hallmark of most types of heart disease and contributes to the progression of heart failure [1]. Multiple signaling pathways have been implicated in the conversion of fibroblasts into myofibroblasts including transforming growth factor β (TGFβ)/mothers against decapentaplegic homolog (Smad), angiotensin II (AngII), endothelin, and winglessrelated integration site (Wnt)/β-catenin [1]. Both angiotensin-converting enzyme inhibitors (ACEIs) and AngII receptor blockers (ARBs) have already shown significant efficacy in reducing cardiac fibrosis in human and animal models of heart failure, they have not been approved for the treatment of cardiac fibrosis [4]. The role of IGF-1/IGF-1R signaling in the development of myocardial interstitial fibrosis under non-ischemic cardiac injury has never been directly addressed
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