EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice

Sci Rep. 2016 Apr 18;6:24580. doi: 10.1038/srep24580.

Abstract

Obesity is often associated with increased risk of cardiovascular diseases. Previous studies suggest that epidermal growth factor receptor (EGFR) antagonism may be effective for the treatment of angiotensin II-induced cardiac hypertrophy and diabetic cardiomyopathy. This study was performed to demonstrate if EGFR plays a role in the pathogenesis of hyperlipidemia/obesity-related cardiac injuries. The in vivo studies using both wild type (WT) and apolipoprotein E (ApoE) knockout mice fed with high fat diet (HFD) showed the beneficial effects of small-molecule EGFR inhibitors, AG1478 and 542, against obesity-induced myocardial injury. Administration of AG1478 and 542 significantly reduced myocardial inflammation, fibrosis, apoptosis, and dysfunction in both two obese mouse models. In vitro, EGFR signaling was blocked by either siRNA silencing or small-molecule EGFR inhibitors in palmitic acid (PA)-stimulated cardiomyocytes. EGFR inhibition attenuated PA-induced inflammatory response and apoptosis in H9C2 cells. Furthermore, we found that PA-induced EGFR activation was mediated by the upstream TLR4 and c-Src. This study has confirmed the detrimental effect of EGFR activation in the pathogenesis of obesity-induced cardiac inflammatory injuries in experimental mice, and has demonstrated the TLR4/c-Src-mediated mechanisms for PA-induced EGFR activation. Our data suggest that EGFR may be a therapeutic target for obesity-related cardiovascular diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Apoptosis
  • Cardiovascular Diseases / drug therapy
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / metabolism*
  • Cell Line
  • Diet, High-Fat / adverse effects
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Hyperlipidemias / complications*
  • Hyperlipidemias / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Palmitic Acid / toxicity
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Rats
  • Toll-Like Receptor 4 / metabolism
  • Tyrphostins / pharmacology
  • Tyrphostins / therapeutic use
  • src-Family Kinases / metabolism

Substances

  • Apolipoproteins E
  • Protein Kinase Inhibitors
  • Quinazolines
  • Toll-Like Receptor 4
  • Tyrphostins
  • RTKI cpd
  • Palmitic Acid
  • EGFR protein, mouse
  • ErbB Receptors
  • src-Family Kinases