TY - JOUR
T1 - Metalloproteinase inhibitor attenuates neointima formation and constrictive remodeling after angioplasty in rats
T2 - Augmentative effect of αvβ3 receptor blockade
AU - Margolin, Leon
AU - Fishbein, Ilia
AU - Banai, Shmuel
AU - Golomb, Gershon
AU - Reich, Reuven
AU - Perez, Louise S.
AU - Gertz, S. David
PY - 2002
Y1 - 2002
N2 - 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 (αvβ3) 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 (αvβ3) blockade, on neointima formation and arterial remodeling in a long-term model (up to 2 1/2 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 αvβ3 receptor inhibiting RGD peptide, G-Pen-GRGDSPCA (GIBCO BRL, 0.1 μmol), 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 2 1/2 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.
AB - 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 (αvβ3) 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 (αvβ3) blockade, on neointima formation and arterial remodeling in a long-term model (up to 2 1/2 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 αvβ3 receptor inhibiting RGD peptide, G-Pen-GRGDSPCA (GIBCO BRL, 0.1 μmol), 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 2 1/2 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.
KW - Angioplasty
KW - Extracellular matrix
KW - Intimal hyperplasia
KW - Matrix metalloproteinase
KW - Restenosis
KW - Vascular remodeling
KW - Vitronectin
UR - http://www.scopus.com/inward/record.url?scp=0036275380&partnerID=8YFLogxK
U2 - 10.1016/S0021-9150(02)00035-7
DO - 10.1016/S0021-9150(02)00035-7
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C2 - 12052473
AN - SCOPUS:0036275380
SN - 0021-9150
VL - 163
SP - 269
EP - 277
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -