TY - JOUR
T1 - Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells
AU - Ishikura, Kenji
AU - Fujita, Hisayo
AU - Hida, Mariko
AU - Awazu, Midori
N1 - Funding Information:
This study was supported by grants from the Ministry of Education, Science and Culture, Japan (070362, 10670757, 12770610, 13770404, 14570772), Pharmacia-Upjohn Fund for Growth and Development Research.
PY - 2005/5/16
Y1 - 2005/5/16
N2 - 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.
AB - 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.
KW - Angioplasty
KW - Forskolin
KW - Protein-serine-threonine kinase
KW - Rho GTP-binding protein
KW - Trapidil
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U2 - 10.1016/j.ejphar.2005.04.013
DO - 10.1016/j.ejphar.2005.04.013
M3 - Article
C2 - 15894306
AN - SCOPUS:20344391382
SN - 0014-2999
VL - 515
SP - 28
EP - 33
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -