Abstract
Migration of medial smooth muscle cells (SMC) into the intima is important in intimal thickening of atherosclerotic tissues. To study the functions of three isoforms of platelet-derived growth factor (PDGF) in atherosclerosis, we investigated their effects on SMC migration by Boyden's chamber method. Although PDGF-AB and PDGF-BB enhanced SMC migration dose-dependently, PDGF-AA did not enhance SMC migration, but instead inhibited SMC migration induced by PDGF-AB or PDGF-BB. PDGF-AA also inhibited SMC migration induced by two other migration factors, fibronectin and SMC-derived migration factor. PDGF-AA is considered to be coexpressed with transforming growth factor (TGF)-beta 1 in atherosclerotic tissues. Treatment of SMC with TGF-beta 1 reduced an autocrine migration activity from SMC. Studies using anti-PDGF antibody revealed that an increased secretion of PDGF-AA by TGF-beta 1 caused the reduced migration activity. cAMP increase by forskolin and dibutyryl cAMP suppressed SMC migration, whereas cAMP decrease by pertussis toxin had no effects on PDGF-AA-suppressed migration. In contrast, staurosporine, an inhibitor of protein kinase C, enhanced SMC migration and neutralized the inhibitory effect of PDGF-AA. These findings suggest that PDGF-AA regulates SMC migration in intimal thickening in atheroma formation and that protein kinase C may play an important role in the inhibitory mechanism of PDGF-AA.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Alkaloids / pharmacology
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Animals
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Aorta, Thoracic / cytology
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / physiology*
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Biological Factors / metabolism
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Biological Factors / pharmacology
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Bucladesine / pharmacology
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Cell Division / drug effects
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Cell Movement / drug effects
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP / physiology
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Dose-Response Relationship, Drug
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Fibronectins / pharmacology
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Isoquinolines / pharmacology
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Kinetics
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Macromolecular Substances
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiology*
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Pertussis Toxin
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Piperazines / pharmacology
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Platelet-Derived Growth Factor / pharmacology*
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Rats
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Rats, Wistar
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Recombinant Proteins / pharmacology
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Second Messenger Systems / drug effects
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Staurosporine
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Sulfonamides / pharmacology
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Tetradecanoylphorbol Acetate / pharmacology
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Transforming Growth Factor beta / pharmacology
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Virulence Factors, Bordetella / pharmacology
Substances
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Alkaloids
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Biological Factors
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Fibronectins
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Isoquinolines
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Macromolecular Substances
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Piperazines
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Platelet-Derived Growth Factor
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Recombinant Proteins
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Sulfonamides
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Transforming Growth Factor beta
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Virulence Factors, Bordetella
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N-(6-phenylhexyl)-5-chloro-1-naphthalenesulfonamide
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Colforsin
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Bucladesine
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Cyclic AMP
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Pertussis Toxin
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Protein Kinase C
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Staurosporine
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Tetradecanoylphorbol Acetate