Role of Rho-Kinase in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stents in Pigs In Vivo

ObjectivesThis study examined whether the Rho-kinase pathway is involved in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents (DES) in pigs in vivo.BackgroundRecent studies showed that coronary vasoconstricting responses are enhanced at the edge of coronary segments implanted with DES compared with bare-metal stents (BMS) in humans. We have previously shown that the activated Rho-kinase pathway plays a central role in the molecular mechanism of coronary vasospasm in animals and humans.MethodsHuman coronary artery smooth muscle cells (hCASMCs) were coincubated with various concentrations of paclitaxel (10−9to 10−6mol/l, corresponding levels reported in DES-implanted arterial tissue) for 24 h. A paclitaxel-eluting stent (PES), sirolimus-eluting stent (SES), and BMS were randomly implanted in the left coronary arteries in pigs for 4 weeks.ResultsIn hCASMCs, paclitaxel significantly enhanced Rho-kinase expression and activity. In a porcine model, coronary vasoconstricting responses to serotonin (10 and 100 μg/kg intracoronary administration) were significantly enhanced at the PES site compared with the BMS site (45 ± 4% vs. 30 ± 3%; p < 0.01; n = 12 each), and were abolished by hydroxyfasudil (90 and 300 μg/kg intracoronary administration), a selective Rho-kinase inhibitor. The PES enhanced inflammatory responses and microthrombus formation at the stent edge, where immunoreactivities for Rho-kinase expression and activity were increased. In organ chamber experiments, serotonin-induced contractions were significantly enhanced in rings from the PES edge site compared with the BMS edge site. The SES also caused similar coronary hyperconstricting responses to serotonin in vivo.ConclusionsThese results suggest that the Rho-kinase pathway plays an important role in the pathogenesis of DES-induced coronary hyperconstricting responses.