The Effect of Gabexate Mesylate in vivo Model of Intimal Hyperplasia on the Activity of Matrix Metalloproteinase and Proliferation of Smooth Muscle Cell

Yang, Ho Cheol; Kwun, Woo Hyung; Suh, Bo Yang; Kwun, Koing Bo

Abstract

PURPOSE
Migration and proliferation of vascular smooth muscle cells (VSMCs) are important for neointimal formation after arterial injury. Migration of VSMCs requires the degradation of basement membrane and extracellular matrix surrounding the cell. There is increasing evidence that VSMCs produce extracellular matrix-degradating proteinases, such as matrix metalloproteinases (MMPs) after arterial injury. METHOD: To assess the effect of gabexate mesylate, an MMP inhibitor, in VSMCs proliferation, migration and intimal thickening, the gelatinolytic activity of MMPs and the expression of VSMC alpha-actin mRNA were analyzed in the balloon-injured rat aorta model. Forty male Sprague-Dawley rats, weighing of 250 to 300 g, underwent aortic intimal denudation with a 2 F balloon catheter. The rats were divided into two groups: the control group (n=20: no medication), and the treatment group (n=20: daily intraperitoneal injection of gabexate mesylate (5.0 mg/kg)). The aorta was harvested at various time intervals, 1, 5, 7, and 21 days after the injury. MMP expression was analyzed by using gelatin zymography, the VSMC alpha-actin mRNA expression was analyzed by RT-PCR, and the intima to media area ratio (IMAR) were evaluated microscopically. RESULT: The treatment group showed significant suppression of intimal hyperplasia compared to the control group on day 21 (P<0.05). Mean IMAR on day 21 were 1.18+/-0.2 in the control group and 0.61+/-0.06 in the treatment group. The gelatinolytic activity of MMP-9 on day 1 after injury was significantly lower in the treatment group compared to the control group (P<0.05). The gelatinolytic activity of activated MMP-2 on days 5, 7, and 21 after injury, decreased significantly in the treatment group compared to the control group (P<0.05). The expression of VSMC alpha-actin mRNA increased on days 7 and 21 after injury. Although the expression of VSMC alpha-actin mRNA was lower in the treatment group, it was not statistically significant.
CONCLUSION
These results suggest that gabexate mesylate suppresses intimal hyperplasia formation after arterial injury by decreasing activation of MMP.