Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Topical
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Animals
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Aorta, Thoracic / cytology
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Aorta, Thoracic / drug effects
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Carotid Artery, Common / pathology
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Catheterization / adverse effects
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Cell Division / drug effects*
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Cells, Cultured
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Dose-Response Relationship, Drug
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Glyceraldehyde-3-Phosphate Dehydrogenases / drug effects
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Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
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Guanylate Cyclase / drug effects
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Guanylate Cyclase / genetics
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Guanylate Cyclase / metabolism
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Indazoles / administration & dosage
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Indazoles / chemistry
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Indazoles / pharmacokinetics*
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Muscle, Smooth, Vascular / cytology*
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / growth & development
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Poloxamer / chemistry
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Poloxamer / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / genetics
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RNA, Messenger
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Rats
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Receptors, Enterotoxin
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Receptors, Guanylate Cyclase-Coupled
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Receptors, Peptide / drug effects
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Receptors, Peptide / genetics
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Receptors, Peptide / metabolism
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism
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Tunica Intima / drug effects
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Tunica Intima / growth & development
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Tunica Intima / pathology
Substances
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Imidazoles
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Indazoles
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RNA, Messenger
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Receptors, Peptide
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Transforming Growth Factor beta
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Poloxamer
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3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
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Glyceraldehyde-3-Phosphate Dehydrogenases
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Ptk2 protein, rat
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Guanylate Cyclase
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Receptors, Enterotoxin
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Receptors, Guanylate Cyclase-Coupled