Metalloproteinase inhibition and the response to angioplasty and stenting in atherosclerotic primates

Abstract

Determinants of restenosis after angioplasty include constrictive remodeling and intimal hyperplasia. Both processes require extensive matrix turnover, so matrix metalloproteinases (MMPs) have become potential targets of antirestenosis therapies. We studied the effects of RO113-2908, a broad-spectrum MMP inhibitor (MMPI), on the response to iliac artery angioplasty and stenting in atherosclerotic cynomolgus monkeys. Lumen diameter (LD) was measured angiographically, and artery wall geometry was assessed after perfusion-fixation at 4 weeks. Angiogenesis was measured in subcutaneous polyvinyl alcohol disks. Treatment provided significant, systemic MMP inhibitory activity (97±2.2% inhibition of 25 nmol/L MMP-12 by serum) and inhibited angiogenesis (P=0.007). In contrast, loss of gain in LD (P=0.73) and constrictive remodeling (external elastic lamina area ratio [injured/uninjured × 100]: MMPI, 106.3±9.6% vs control, 119.9±7.2%; P=0.27) were not substantially improved 4 weeks after angioplasty. Treatment also failed to reduce intimal hyperplasia after angioplasty (intimal area [mm2]: 1.4±0.3 vs 1.6±0.2, P=0.65) or stenting (2.4±0.2 vs 2.8±0.2, P=0.12). In summary, inhibition of MMP activity reduced angiogenesis but failed to prevent constrictive remodeling or intimal hyperplasia after angioplasty and stenting in atherosclerotic primates. Additional research is needed to define the spectrum of matrix-degrading proteases critical in healing atherosclerotic arteries after angioplasty.