The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury.
Proliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis. We investigated whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [(3)H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Ras- and ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury.
Peng
Chieh-Yu
CY
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
Pan
Shiow-Lin
SL
Guh
Jih-Hwa
JH
Liu
Yi-Nan
YN
Chang
Ya-Ling
YL
Kuo
Sheng-Chu
SC
Lee
Fang-Yu
FY
Teng
Che-Ming
CM
D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001161:Arteriosclerosis / Q000473:pathology; D015153:Blotting, Western; D002404:Catheterization / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008956:Models, Chemical; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C412964:1-benzyl-3-(ethoxycarbonylpheny)-indazole; D005419:Flavonoids; D007191:Indazoles; D010455:Peptides; D047428:Protein Kinase Inhibitors; D044463:Receptor, PAR-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D013936:Thymidine