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.
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| Abstract |
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-NH(2) by recombinant MMP-2 and MMP-9 with IC(50) values = 2.07 and 8.20 muM, 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.
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| Authors | Yi-Nan Liu, Shiow-Lin Pan, Chieh-Yu Peng, Jih-Hwa Guh, Dong-Ming Huang, Ya-Ling Chang, Chun-Hung Lin, Hui-Chen Pai, Sheng-Chu Kuo, Fang-Yu Lee, Che-Ming Teng |
| Journal | The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 316 Issue 1 Pg. 35-41 (Jan 2006) ISSN: 0022-3565 [Print] United States |
| PMID | 16183705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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