Abstract 15916: EGF-Like Ligands Contribute to Neointimal Formation via Nox1-Mediated SMC Growth
Chronic inflammation is associated with extracellular oxidative stress and accelerated vascular disease. We have reported that a more oxidized extracellular redox state promotes epidermal growth factor (EGF)-like ligand shedding, resulting in EGFR-mediated increase in expression of Nox1 NADPH oxidase and proliferation of smooth muscle cells (SMC). Furthermore, we observed increased plasma levels of EGF-like ligands, particularly HB-EGF, in a non-human primate model of atherosclerosis. We hypothesized that EGF-like ligands contribute to the development of vascular disease by promoting Nox1-mediated SMC growth. In cultured SMCs, treatment with HB-EGF increased Nox1 transcription and SMC proliferation. Expression of siRNA to Nox1, but not Nox4, prevented HB-EGF-induced cell growth. The mitochondria-targeted antioxidant MitoTEMPO inhibited HB-EGF-mediated Nox1 expression and SMC proliferation. Furthermore, overexpression of Nox1 restored HB-EGF-mediated proliferation in the presence of MitoTEMPO. We next implanted osmotic minipumps containing HB-EGF into 16-wk old hypercholesterolemic mice and 2d later performed carotid ligation as a model of vascular injury. Two weeks following ligation, mice receiving HB-EGF demonstrated a 60% increase in plasma HB-EGF, 65% increase in aortic expression of Nox1, and a 55% increase in carotid intimal area (I/M ratio 0.52±0.01 vs. 0.91±0.01, p<0.01) as compared to control mice. Nox4 and serum cholesterol levels were unchanged by increased circulating HB-EGF. Finally, we examined whether cardiac allograft vasculopathy was associated with plasma EGF-like ligand levels. Cardiac transplant patients (ejection fraction >50%) were divided into two groups based on the severity of allograft vasculopathy as determined by angiography. HB-EGF levels positively correlated with disease severity, with circulating concentrations 1.9-fold higher in patients with moderate to severe coronary disease as compared to patients with absent to mild disease (n=9/group; p<0.05). Taken together, these findings suggest that conditions associated with increased circulating EGF-like ligands contribute to the acceleration of vascular disease by a mechanism that involves mitochondrial ROS and expression of Nox1.
- © 2013 by American Heart Association, Inc.