The inhibitory mechanism of YC-1, a benzyl indazole, on smooth muscle cell proliferation: an in vitro and in vivo study.
The pharmacological mechanisms of a synthetic compound 1-benzyl-3-(5'-hydroxymethyl-2'-furyl) indazole (YC-1) in preventing smooth muscle cell proliferation remains to be elucidated. The present study was aimed to explore the effects of YC-1 on certain molecules responsible for cell proliferation, including transforming growth factor (TGF)-beta1, soluble guanylyl cyclase (sGC) and focal adhesion kinase (FAK). The in vivo assay was correlated to the in vitro results of YC-1 on vascular stenosis. YC-1 was applied topically via a pluronic gel onto the balloon-injured rat carotid arteries, which were then harvested two weeks later for histological analysis. Our in vitro results showed that TGF-beta1 was suppressed by YC-1 by 50%. The translational level of sGC was threefold activated by YC-1 while the transcription level of sGC was increased up to 24-fold. FAK, the molecule responsible for cell proliferation and migration, was suppressed by YC-1 on the translational levels for 72%. These in vitro results were in consistent with the in vivo observation that the area ratio of neointima to media was reduced by YC-1. This study provides insights into the pharmacological mechanisms of YC-1 in preventing abnormal smooth muscle cell proliferation and thus supports the use of YC-1 as an adjuvant therapy for balloon injury-induced restenosis.
Wu
Chieh-Hsi
CH
Department of Pharmacology, China Medical University, Taichung, Taiwan. chhswu@mail.cmu.edu.tw
Chang
Weng-Cheng
WC
Chang
Gee-Yat
GY
Kuo
Sheng-Chu
SC
Teng
Che-Ming
CM
D000287:Administration, Topical; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D017536:Carotid Artery, Common / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000187:drug effects / Q000235:genetics; D006162:Guanylate Cyclase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000254:growth & development; D020442:Poloxamer / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger; D051381:Rats; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development / Q000473:pathology
D007093:Imidazoles; D007191:Indazoles; D012333:RNA, Messenger; D018000:Receptors, Peptide; D016212:Transforming Growth Factor beta; D020442:Poloxamer; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled