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

PLoS One. 2017 Jun 1;12(6):e0178619. doi: 10.1371/journal.pone.0178619. eCollection 2017.

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.

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Echocardiography
  • Fibrosis / prevention & control
  • Gene Expression / drug effects
  • Heart Diseases / chemically induced
  • Heart Diseases / diagnostic imaging
  • Heart Diseases / genetics
  • Heart Diseases / prevention & control*
  • Imatinib Mesylate / pharmacology*
  • Isoproterenol / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Ventricular Remodeling

Substances

  • Imatinib Mesylate
  • Receptors, Platelet-Derived Growth Factor
  • Isoproterenol

Grants and funding

This work was supported by National Natural Science Funds of China (Grant No.81370215 and 81570039; URL: http://www.nsfc.gov.cn/) and China Postdoctoral Science Foundation (Grant No.2016M590838; URL: http://jj.chinapostdoctor.org.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.