Adenovirus-mediated transfer of dominant-negative Rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo

Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin c ytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that ad enovirus-mediated transfer of dominant-negative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coro nary vasospastic activity in vivo. Porcine coronary segments were chronical ly treated with interleukin-1 beta which resulted in the development of con strictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of beta -gal actosidase, into the interleukin-1 beta -treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospas tic activity in 3 weeks. Western blot analysis showed that the phosphorylat ion of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRhoK. These results indicate that Rho-kina se is substantially involved in coronary constrictive remodeling and vasosp astic responses, both of which can be reversed by the selective inhibition of the molecule in our porcine model in vivo.