Imatinib attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors activation in isoproterenol induced model

Abstract

Cardiac fibrosis is a significant global health problem with limited treatment choices. Although previous studies have shown that imatinib (IMA) inhibited cardiac fibrosis, the anti-fibrotic mechanisms have not been clearly uncovered. The aim of this study is to evaluate whether IMA attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors (PDGFR) on isoproterenol (ISO)-induced mice. Adult male C57BL/6 mice were treated with vehicle or ISO ± IMA for one week. After echocardiography examination, the hearts of mice were used for histopathologic, RT-qPCR, and western blot analyses. We found that the ventricular wall thickness, cardiac hypertrophy, and apoptosis were enhanced following ISO treatment. IMA decreased the left ventricular wall thickness, prevented hypertrophy, and inhibited apoptosis induced by ISO. In addition, IMA attenuated the accumulation of collagens and α-smooth muscle actin (α-SMA) (the markers of fibrosis) caused by ISO treatment. Moreover, the expression of fibrosis related genes, and the phosphorylation of PDGFRs in ISO-treated mice hearts were inhibited by IMA as well. However, IMA did not change the expression of the matrix metalloproteinase-9 (MMP-9) in ISO-treated hearts. Furthermore, IMA reduced the expressions of collagens as well as α-SMA caused by activation of PDGFRα in cardiac fibroblasts. Taken together, our data demonstrate that IMA attenuated the cardiac fibrosis by blocking the phosphorylation of PDGFRs in the ISO-induced mice model. This study indicates that IMA could be a potentially therapeutic option for cardiac fibrosis in clinical application.

TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway

“…Isoproterenol stimulation to create myocardial injury. To examine cardiac tolerance in a stress environment, we used the isoproterenol-induced myocardial injury model as previously described [11][12][13][14]. Isoproterenol hydrochloride, a synthetic non-selective β-adrenergic agonist, was dissolved in physiological saline.…”

Platelet Derived Growth Factor Alpha (PDGFRα) Induces the Activation of Cardiac Fibroblasts by Activating c-Kit

“…In our previous study [ 22 ], we found that the PDGF-A expression was significantly increased in the ISO group model heart, and the kinase activity of PDGFRα also was enhanced in the heart of the cardiac fibrosis model. PDGF-AA (activated form of PDGF-A) treatment could activate the fibroblasts by binding and activating PDGFRα [ 25 ].…”

“…In our previous study [ 22 ], we successfully constructed a mice model of cardiac fibrosis using ISO. To assess the activity changes of c-Kit in a cardiac fibrosis model, we tested the phosphorylation state of c-Kit (p-Kit: Tyr719) in the hearts of cardiac fibrosis model mice by western blotting.…”

“…A cardiac fibrosis mice model was established and treated as described previously [ 22 ]. Briefly, C57BL/6 mice (10–12 weeks old, male) were randomly divided into four groups: vehicle (PBS), isoproterenol (ISO) (20 mg/kg, subcutaneous injection daily) (Sigma-Aldrich, USA), imatinib (40 mg/kg, intraperitoneal injection daily) (MedChem Express, USA), and ISO + imatinib for one week.…”

RASSF1‐AS1, an antisense lncRNA of RASSF1A, inhibits the translation of RASSF1A to exacerbate cardiac fibrosis in mice

“…Col‐I is produced mainly by fibroblasts, it plays an important role in homeostasis in normal tissue and cell growth, invasion, and metastasis in cancer tissue (Kong et al, ). α‐SMA is overexpressed in local fibroblasts (Wang et al, ). These results demonstrated that RASSF1‐AS1 exacerbated cardiac fibroblast activation and inflammation in vitro, but RASSF1‐AS1‐del could not.…”