Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells.
Trapidil suppresses platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell (VSMC) proliferation by inhibiting Raf-1/extracellular signal-regulated kinase (ERK) via cAMP/protein kinase A (PKA). We examined whether trapidil inhibits PDGF-induced VSMC migration and investigated its mechanisms of action. VSMC migration was inhibited to a similar extent by trapidil and forskolin. A PKA inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H89) blocked the inhibition by forskolin to a greater degree than that by trapidil. Trapidil but not forskolin suppressed PDGF-stimulated RhoA activation. In the presence of both H89 and (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride monohydrate, an inhibitor of Rho-associated kinase (ROCK), trapidil and forskolin inhibited migration to a similar extent. Thus, in addition to cAMP/PKA activation, trapidil inhibits RhoA/ROCK activation, which may be important in trapidil's inhibitory effect on migration.
Ishikura
Kenji
K
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Fujita
Hisayo
H
Hida
Mariko
M
Awazu
Midori
M
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014192:Trapidil / Q000494:pharmacology*; D014316:Tritium; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000577:Amides; D004798:Enzymes; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D013449:Sulfonamides; D014316:Tritium; C108830:Y 27632; D005576:Colforsin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein; D014192:Trapidil; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013936:Thymidine