batimastat and Constriction--Pathologic

Release of matrix metalloproteinases (MMP) from smooth muscle and foam cells following arterial injury facilitates cell migration, neointimal hyperplasia, and vessel wall remodeling. Inhibition of MMP activity using the hydroxamate, zinc-chelating mimicers of collagen, Batimastat and Marimastat, has shown efficacy in reducing constrictive vascular remodeling 6 weeks after experimental angioplasty but not intimal hyperplasia. Vitronectin receptor (alpha(v)beta(3)) blockade interferes with binding of this integrin to MMP-2 and proteolyzed collagen, thereby reducing cell invasion. This study tests the effect of MMP inhibition, with and without vitronectin receptor (alpha(v)beta(3)) blockade, on neointima formation and arterial remodeling in a long-term model (up to 212 months) of balloon injury in vivo. Male Sabra rats were treated with Batimastat (BB-94, British Biotech Pharmaceuticals Ltd., 30 mg/kg, intraperitoneally) and/or the alpha(v)beta(3) receptor inhibiting RGD peptide, G-Pen-GRGDSPCA (GIBCO BRL, 0.1 micromol), administered as a perivascular gel to the common carotid artery after balloon injury. Animals were sacrificed 3, 14, 25, and 75 days (n=21, 23, 22, and 21) after injury. Animals treated with BB-94, peptide, or both had markedly increased absolute luminal area with markedly reduced luminal cross-sectional-area narrowing by neointima and intima-to-media area ratio at all time points except for 3 days after balloon injury versus non-treated, ballooned animals. Combined treatment was significantly more effective than either one alone. Constrictive remodeling, most marked 212 months after balloon injury, was prevented at this time point in all treated animals. The pattern of reduction in luminal narrowing, neointimal formation, and constrictive remodeling across treatment groups correlated very significantly with the reduction in tissue MMP activity as determined by zymography at 3 days. Confirmation of the efficacy of this strategy in larger animals should be the next step toward testing the applicability of this novel approach to the interventional setting.

Topics: Angioplasty, Balloon; Animals; Arteries; Cell Movement; Constriction, Pathologic; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Hydroxamic Acids; Hyperplasia; Male; Matrix Metalloproteinase Inhibitors; Muscle, Smooth, Vascular; Oligopeptides; Phenylalanine; Rats; Receptors, Vitronectin; Thiophenes; Tunica Intima