Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II

J Cell Mol Med. 2016 Mar;20(3):482-94. doi: 10.1111/jcmm.12763. Epub 2016 Jan 14.

Abstract

Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)-induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal-regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II-induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II-induced EGFR activation is mediated by c-Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c-Src-dependent EGFR activation may play an important role in Ang II-induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II-associated cardiac diseases.

Keywords: angiotensin II; c-Src; cardiac hypertrophy; epidermal growth factor receptor; small-molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Cardiomegaly / chemically induced
  • Cardiomegaly / drug therapy*
  • Cardiotonic Agents / pharmacology*
  • Cardiotonic Agents / therapeutic use
  • Cell Line
  • Drug Evaluation, Preclinical
  • Epidermal Growth Factor / physiology
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Knockdown Techniques
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Rats
  • Tyrphostins / pharmacology*
  • Tyrphostins / therapeutic use

Substances

  • Cardiotonic Agents
  • Quinazolines
  • Tyrphostins
  • Angiotensin II
  • RTKI cpd
  • Epidermal Growth Factor
  • EGFR protein, mouse
  • ErbB Receptors