The kinase inhibitor fasudil (HA-1077) reduces intimal hyperplasia through inhibiting migration and enhancing cell loss of vascular smooth muscle cells.
Smooth muscle cell (SMC) migration plays an important role in restenosis after angioplasty. Myosin phosphorylation is necessary for cell migration. Fasudil is an inhibitor of protein kinases, including myosin light chain kinase and Rho associated kinase, thereby inhibiting myosin phosphorylation, and it has been clinically used to prevent vasospasm following subarachnoid hemorrage. Based on these findings, we examined the anti-migrative action of fasudil. In SMC (SM-3), fasudil (1-100 microM) inhibited SMC migration in a dose-dependent manner (p < 0.001). Fasudil suppressed actin stress fiber formation dose dependently. In rabbit carotid artery, fasudil (10 mg/kg/day) markedly reduced intimal hyperplasia 14 days following balloon injury. Cell kinetic study showed that fasudil did not affect proliferation but enhanced cell loss in the media after injury. We concluded that fasudil reduced neointimal formation after balloon injury through both inhibiting migration and enhancing cell loss of medial SMC.
Negoro
N
N
First Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki City, Osaka, 569-8686, Japan.
Hoshiga
M
M
Seto
M
M
Kohbayashi
E
E
Ii
M
M
Fukui
R
R
Shibata
N
N
Nakakoji
T
T
Nishiguchi
F
F
Sasaki
Y
Y
Ishihara
T
T
Ohsawa
N
N
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta; D020212:Carotid Artery Injuries; D002404:Catheterization; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D047428:Protein Kinase Inhibitors; D011817:Rabbits; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects
D000199:Actins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil