Stent implantation activates RhoA in human arteries: inhibitory effect of rapamycin.
In-stent restenosis is a novel pathobiologic process resulting from vascular smooth muscle cell (VSMC) proliferation, migration and excessive matrix production. The present study was designed to assess the activity of RhoA, a major regulator of VSMC proliferation and migration, after stenting and to determine its role in the neointimal formation. Analysis of RhoA activity in an ex vivo organ culture model of human internal mammary arteries demonstrates that stenting induced a time-dependent increase in RhoA activity (4.9 +/- 0.4 vs. 1.2 +/- 0.2 in control at 28 days, n = 4, p < 0.0001) associated with a concomitant decrease in p27 expression. Treatment of stented arteries with the permeant RhoA inhibitor TAT-C3 (10 microg/ml) or Rho-kinase inhibitors (Y-27632, 10 micromol/l; fasudil, 10 micromol/l) inhibited both neointimal formation and decrease in p27 expression. Rapamycin (1 and 10 nmol/l) also inhibited neointimal formation, and induced a loss of RhoA expression. The inhibitory effect of rapamycin on neointimal thickening is prevented by the dominant active form of RhoA. Our study shows that stent implantation induces maintained RhoA activation and demonstrates that the inhibitory action of rapamycin on RhoA expression plays a key role in its antirestenotic effect.
Guérin
Patrice
P
INSERM U 533, Faculté des Sciences, Nantes, France.
Sauzeau
Vincent
V
Rolli-Derkinderen
Malvyne
M
Al Habbash
Oussama
O
Scalbert
Elizabeth
E
Crochet
Dominique
D
Pacaud
Pierre
P
Loirand
Gervaise
G
D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D018797:Cell Cycle Proteins / Q000032:analysis; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006801:Humans; D008323:Mammary Arteries / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D015607:Stents / Q000009:adverse effects*; D025521:Tumor Suppressor Proteins / Q000032:analysis; D017539:Tunica Intima / Q000473:pathology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000502:physiology
D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020742:rhoA GTP-Binding Protein; D020123:Sirolimus