The β3 Integrin Antagonist m7E3 Reduces Matrix Metalloproteinase Activity and Smooth Muscle Cell Migration

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Abstract
Treatment with c7E3 (abciximab, ReoPro) has been associated with a reduction in coronary events and the need for revascularization. Some of these beneficial effects may be due to blockade of the αvβ3 integrin receptor on smooth muscle cells (SMCs), however very little is known about the mechanisms involved. The current studies were designed to test the hypothesis that β3 integrin antagonists inhibit the arterial response to injury by reducing matrix metalloproteinase (MMP) activity in the vessel wall. Male Sprague-Dawley rats were treated with daily intraperitoneal injections of the monoclonal antibody m7E3 at a dose of 6 mg/kg/day. MMP-9 activity was reduced by 73%, and MMP-2 activity by 75%, in the injured carotids of the m7E3-treated rats compared to saline-treated controls. By contrast, tissue inhibitor metalloproteinase (TIMP) activity was not changed. SMC migration assayed at 4 days after injury was reduced from 56.7 ± 14 cells/mm2 intimal surface area in controls to 17.5 ± 5 cells/mm2 in m7E3-treated rats (p = 0.02). Medial cell replication measured at 4 days and intimal cell replication measured at 7 days were not affected. Intimal cross-sectional area, measured 14 days after injury was reduced by 28% after m7E3 treatment (p = 0.05). Intimal smooth muscle cell number and the ratio of intima/media cross-section area were also reduced. By contrast, intimal SMC density was not affected by m7E3 treatment, indicating no effect on matrix accumulation. We conclude that treatment with m7E3 reduced SMC migration following vascular injury, possibly via an inhibitory effect on MMP activity, and this resulted in a decrease in intimal size at 14 days after injury.