Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo

Hiroaki Shimokawa, Kunio Morishige, Kenji Miyata, Tadashi Kandabashi, Yasuhiro Eto, Ichiro Ikegaki, Toshio Asano, Kozo Kaibuchi, Akira Takeshita

研究成果: Article査読

95 被引用数 (Scopus)

抄録

Objective: We recently demonstrated that Rho-kinase/ROK/ROCK is functionally upregulated at the arteriosclerotic coronary lesions and plays a key role for coronary vasospastic responses in our porcine model with interleukin (IL)-1β. In the present study, we tested our hypothesis that Rho-kinase is involved in the pathogenesis of coronary arteriosclerosis per se in our porcine model. Methods: Segments of the left porcine coronary artery were chronically treated from the adventitia with IL-1β. Two weeks after the procedure, coronary stenotic lesions with constrictive remodeling and vasospastic response to serotonin were noted at the IL-1β-treated site, as previously reported. Then, animals were randomly divided into two groups; one group was treated with fasudil for 8 weeks followed by 1 or 4 weeks of washout period and another group served as a control. After oral absorption, fasudil is metabolized to hydroxyfasudil that is a specific inhibitor of Rho-kinase. Results: In the fasudil group, coronary stenosis and vasospastic response were progressively reduced in vivo, while the coronary hyperreactivity was abolished both in vivo and in vitro. Furthermore, Western blot analysis showed that in the fasudil group, the Rho-kinase activity (as evaluated by the extent of phosphorylation of myosin binding subunit of myosin phosphatase, one of the major substrates of Rho-kinase) was significantly reduced, while histological examination demonstrated a marked regression of the coronary constrictive remodeling. Conclusions: These results indicate that Rho-kinase is substantially involved in constrictive remodeling and vasospastic activity of the arteriosclerotic coronary artery, both of which could be reversed by long-term inhibition of the molecule in vivo. Thus, Rho-kinase may be regarded as a novel therapeutic target for arteriosclerotic vascular disease.

本文言語English
ページ(範囲)169-177
ページ数9
ジャーナルCardiovascular Research
51
1
DOI
出版ステータスPublished - 2001
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生理学
  • 循環器および心血管医学
  • 生理学(医学)

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