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.
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.
Liu
Yi-Nan
YN
Pharmacological Institute, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Sect. 1, Taipei, Taiwan.
Pan
Shiow-Lin
SL
Peng
Chieh-Yu
CY
Guh
Jih-Hwa
JH
Huang
Dong-Ming
DM
Chang
Ya-Ling
YL
Lin
Chun-Hung
CH
Pai
Hui-Chen
HC
Kuo
Sheng-Chu
SC
Lee
Fang-Yu
FY
Teng
Che-Ming
CM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002339:Carotid Arteries / Q000473:pathology*; D002404:Catheterization; D006152:Cyclic GMP / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020533:Angiogenesis Inhibitors; D005456:Fluorescent Dyes; D007191:Indazoles; D012333:RNA, Messenger; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006152:Cyclic GMP