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

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

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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-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.

Original languageEnglish
Pages (from-to)35-41
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume316
Issue number1
DOIs
Publication statusPublished - Jan 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

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