Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β

Tadashi Kandabashi, Hiroaki Shimokawa, Kenji Miyata, Ikuko Kunihiro, Yoji Kawano, Yuko Fukata, Taiki Higo, Kensuke Egashira, Shosuke Takahashi, Kozo Kaibuchi, Akira Takeshita

Research output: Contribution to journalArticlepeer-review

220 Citations (Scopus)

Abstract

Background - We recently demonstrated that the Rho-kinase-mediated pathway plays an important role for coronary artery spasm in our porcine model with interleukin-1β (IL-1β). In this study, we examined whether or not Rho-kinase is upregulated at the spastic site and if so, how it induces vascular smooth muscle hypercontraction. Methods and Results - Segments of the left porcine coronary artery were chronically treated from the adventitia with IL-1β-bound microbeads. Two weeks after the operation, as reported previously, intracoronary serotonin repeatedly induced coronary hypercontractions at the IL-1β-treated site both in vivo and in vitro, which were markedly inhibited by Y-27632, one of the specific inhibitors of Rho- kinase. Reverse transcription-polymerase chain reaction analysis demonstrated that the expression of Rho-kinase mRNA was significantly increased in the spastic compared with the control segment. Western blot analysis showed that during the serotonin-induced cotractions, the extent of phosphorylation of the myosin-binding subunit of myosin phosphatase (MBS), one of the major substrates of Rho-kinase, was significantly greater in the spastic than in the control segment and that the increase in MBS phosphorylations was also markedly inhibited by Y-27632. There was a highly significant correlation between the extent of MBS phosphorylations and that of contractions. Conclusions - These results indicate that Rho-kinase is upregulated at the spastic site and plays a key role in inducing vascular smooth muscle hypercontraction by inhibiting myosin phosphatase through the phosphorylation of MBS in our porcine model.

Original languageEnglish
Pages (from-to)1319-1323
Number of pages5
JournalCirculation
Volume101
Issue number11
DOIs
Publication statusPublished - Mar 21 2000

Keywords

  • Kinase
  • Muscle, smooth
  • Myosin
  • Phosphorylation
  • Vasospasm

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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