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.
Highlights
Epidermal growth factor receptor (EGFR), named ErbB1 receptor, is a receptor tyrosine kinase that is expressed in various tissues and mediates cell proliferation, differentiation, migration and survival[7]
Mouse heart weight to tibial length ratio was increased under high fat diet (HFD) (Table 1), and histological analysis by Hematoxylin and Eosin (H&E) and Masson staining of cardiac sections showed disordered cardiac muscle fibers and increased myocardial fibrosis in apolipoprotein E (ApoE)-HFD heart, suggesting cardiac hypertrophy and remodeling
The cardiac gene expression levels of fibrotic factors, including Transforming Growth Factor (TGF)-β, Collage I and connective tissue growth factor (CTGF), were all decreased upon AG or 542 treatment compared to ApoE-HFD alone
Summary
Epidermal growth factor receptor (EGFR), named ErbB1 receptor, is a receptor tyrosine kinase that is expressed in various tissues and mediates cell proliferation, differentiation, migration and survival[7]. EGFR signaling pathway is essential for cardiac growth and development[10,11]. Inhibition of EGFR by specific tyrosine kinase inhibitor AG1478 significantly decreases the angiotensin II-mediated synthesis of Transforming Growth Factor (TGF)-β and fibronectin by cardiac fibroblasts[15]. Our group found that EGFR inhibition significantly attenuated streptozotocin-induced diabetic heart injuries[16]. These studies suggest that EGFR antagonism may be an effective drug target for cardiac hypertrophy and remodeling. It is unknown if EGFR play a role in the pathogenesis of obesity-related cardiac injury. Our results contribute to understand the detrimental role and mechanism of EGFR activation in obesity-related cardiac disorders
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