Abstract 272: Epidermal Growth Factor Dependent Collagen Loss in Human Carotid Plaques is Mediated by Matrix Metalloproteinase-9
Aims Atherogenesis is a chronic progressive process that develops over several decades. Changes in the structure and composition of extracellular matrix (ECM) play an important role in the process of atherosclerosis. Matrix metalloproteinases (MMPs) and growth factors present in atherosclerotic human plaques could be related to plaque remodeling and increased risk for plaque destabilization and rupture.
Hypothesis Selective inhibition of elevated MMP-9 and epidermal growth factor receptor (EGFR) increases fibrillar collagens (Type I and III) in vascular smooth muscle cells (VSMCs) from symptomatic (S) and asymptomatic (AS) patients with carotid stenosis.
Methods and results Cultured human VSMCs from both AS and S patients were treated with or without epidermal growth factor (EGF). The proteolytic activity of MMP-9 and MMP-2 was quantified by gelatin zymography. The mRNA transcripts of MMP-9, MMP-1, EGFR and collagen types I (COL1A1 and COL1A2) and III (COL3A1) were analyzed by qPCR. EGF treatment significantly increased MMP-9 activity and mRNA transcripts for MMP-9, MMP-1and EGFR, while mRNA transcripts for collagen types I and III were decreased in both AS and S groups. Collagen type I and type III mRNA transcripts were significantly decreased in symptomatic VSMCs compared to cells from AS. Inhibition of EGFR with AG1478 and MMP-9 using small molecule inhibitor and transfection with MMP-9 siRNA decreased the activity and mRNA expression of MMP-9 and increased mRNA transcripts of collagen I and III in EGF treated VSMCs.
Conclusion These results reveal a novel mechanism by which MMP-9 induced by EGFR activation could be a leading cause of plaque instability in patients with carotid stenosis; and the selective blockade of EGFR and MMP-9 may be a novel strategy and a promising target for treating human unstable and vulnerable plaques.
- © 2013 by American Heart Association, Inc.