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

Objective: We recently demonstrated that Rho-kinase/ROK/ROCK is functionall y upregulated at the arteriosclerotic coronary lesions and plays a key role for coronary vasospastic responses in our porcine model with interleukin ( IL)-1 beta. 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 c hronically treated from the adventitia with IL-1 beta. Two weeks after the procedure, coronary stenotic lesions with constrictive remodeling and vasos pastic response to serotonin were noted at the IL-1 beta -treated site, as previously reported. Then, animals were randomly divided into two groups; o ne group was treated with fasudil for 8 weeks followed by 1 or 4 weeks of w ashout period and another group served as a control. After oral absorption, fasudil is metabolized to hydroxyfasudil that is a specific inhibitor of R ho-kinase. Results: In the fasudil group, coronary stenosis and vasospastic response were progressively reduced in vivo, while the coronary hyperreact ivity was abolished both in vivo and in vitro. Furthermore, Western blot an alysis showed that in the fasudil group, the Rho-kinase activity las evalua ted by the extent of phosphorylation of myosin binding subunit of myosin ph osphatase, one of the major substrates of Rho-kinase) was significantly red uced, while histological examination demonstrated a marked regression of th e coronary constrictive remodeling. Conclusions: These results indicate tha t Rho-kinase is substantially involved in constrictive remodeling and vasos pastic activity of the arteriosclerotic coronary artery, both of which coul d be reversed by long-term inhibition of the molecule in vivo. Thus, Rho-ki nase may be regarded as a novel therapeutic target for arteriosclerotic vas cular disease. (C) 2001 Elsevier Science B.V. All rights reserved.