PT  - JOURNAL ARTICLE
AU  - Liu, Yi-Nan
AU  - Pan, Shiow-Lin
AU  - Peng, Chieh-Yu
AU  - Guh, Jih-Hwa
AU  - Huang, Dong-Ming
AU  - Chang, Ya-Ling
AU  - Lin, Chun-Hung
AU  - Pai, Hui-Chen
AU  - Kuo, Sheng-Chu
AU  - Lee, Fang-Yu
AU  - Teng, Che-Ming
TI  - 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
AID  - 10.1124/jpet.105.090563
DP  - 2006 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 35--41
VI  - 316
IP  - 1
4099  - http://jpet.aspetjournals.org/content/316/1/35.short
4100  - http://jpet.aspetjournals.org/content/316/1/35.full
SO  - J Pharmacol Exp Ther2006 Jan 01; 316
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics