In vivo gene transfer of dominant-negative rho-kinase induces regression of coronary arteriosclerosis in pigs.

Small GTPase Rho and its target Rho-kinase play an important role in various cellular functions that may be involved in the pathogenesis of arteriosclerosis. Here we show that adenovirus-mediated transfer of dominant-negative Rho-kinase (AdDNRhoK) induces a regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1,beta which resulted in the development of constrictive remodeling and vasospastic responses to serotonin in vivo. AdDNRhoK, but not that of beta-galactosidase, into the interleukin-1beta-treated coronary segment caused regression of constrictive remodeling and abolished vasospastic activity in 3 weeks. The unregulated phosphorylation of the target proteins of Rho-kinase at the coronary lesion was significantly suppressed by AdDNRhoK. These results indicate that Rho-kinase is substantially involved in the mechanism of coronary arteriosclerosis, which can be reversed by selective inhibition of the molecule in our porcine model in vivo.