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CARDIOVASCULAR

YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] Inhibits Neointima Formation in Balloon-Injured Rat Carotid through Suppression of Expressions and Activities of Matrix Metalloproteinases 2 and 9

Phamacological Institute (Y.-N.L., S.-L.P., C.-Y.P., D.-M.H., Y.-L.C., C.-H.L., H.-C.P., C.-M.T.), College of Medicine, National Taiwan University, Taipei, Taiwan; School of Pharmacy (J.-H.G.), College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Pharmaceutical Chemistry (S.-C.K.), China Medical University, Taichung, Taiwan; and Yung-Shin Pharmaceutical Industry Co., Ltd. (F.-Y.L.), Taichung, Taiwan

Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and postrevascularization production of vascular smooth muscle cells may play key roles in development of arterial restenosis. We investigated the inhibitory effect of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a benzyl indazole compound, on MMP-2 and MMP-9 activity in a balloon-injury rat carotid artery model. Injury was induced by inserting a balloon catheter through the common carotid artery; after 14 days, histopathological analysis using immunostaining and Western blotting revealed significant restenosis with neointimal formation that was associated with enhanced protein expression of MMP-2 and MMP-9. However, these effects were dose-dependently reduced by orally administered YC-1 (1–10 mg/kg). In addition, gelatin zymography demonstrated that increased MMP-2 and MMP-9 activity was diminished by YC-1 treatment. On the other hand, YC-1 inhibited hydrolysis of the fluorogenic quenching substrate Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂ by recombinant MMP-2 and MMP-9 with IC₅₀ values = 2.07 and 8.20 µM, respectively. Reverse transcription-polymerase chain reaction analysis of MMP-2 and MMP-9 mRNA revealed that YC-1 significantly inhibited mRNA levels of MMPs. Finally, for the YC-1 treatment group, we did not observe elevation of cGMP levels using enzyme-linked immunosorbent assay, suggesting that YC-1 inhibition of neointimal formation is not through a cGMP-elevating pathway. These data show YC-1 suppression of neointimal formation is dependent on its influence on MMP-2 and MMP-9 protein, mRNA expression, and activity, but not through a cGMP-elevating effect. YC-1 shows therapeutic potential for treatment of restenosis after angioplasty.

Address correspondence to: Dr. Che-Ming Teng, Pharmacological Institute, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Sect. 1, Taipei, Taiwan. E-mail: cmteng{at}ha.mc.ntu.edu.tw

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