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PRE-CLINICAL RESEARCH

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

Takashi Shiroto, MD^_*, Satoshi Yasuda, MD, PhD^_*,_*, Ryuji Tsuburaya, MD^_*, Yoshitaka Ito, MD^_*, Jun Takahashi, MD, PhD^_*, Kenta Ito, MD, PhD^_*, Hatsue Ishibashi-Ueda, MD, PhD and Hiroaki Shimokawa, MD, PhD^_*

^_* Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Department of Pathology, National Cardiovascular Center, Suita, Osaka, Japan

Manuscript received April 13, 2009; revised manuscript received June 12, 2009, accepted July 1, 2009.

^_* Reprint requests and correspondence: Dr. Satoshi Yasuda, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan (Email: syasuda{at}cardio.med.tohoku.ac.jp).

Objectives: This 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.

Background: Recent 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.

Methods: Human coronary artery smooth muscle cells (hCASMCs) were coincubated with various concentrations of paclitaxel (10^–9 to 10^–6 mol/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.

Results: In 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.

Conclusions: These results suggest that the Rho-kinase pathway plays an important role in the pathogenesis of DES-induced coronary hyperconstricting responses.

Key Words: vasoconstriction • stents • smooth muscle • inflammation

Abbreviations and Acronyms   BMS = bare-metal stent(s)   CAG = coronary angiography   DES = drug-eluting stent(s)   ERM = ezrin/radixin/moesin   hCASMC = human coronary artery smooth muscle cell   IC = intracoronary administration   MYPT1 = myosin phosphatase target subunit 1   PES = paclitaxel-eluting stent(s)   RNA = ribonucleic acid   ROCK1 = Rho-kinase beta   ROCK2 = Rho-kinase alpha   SES = sirolimus-eluting stent(s)   VSMC = vascular smooth muscle cell

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