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.
Morishige
K
K
Department of Cardiovascular Medicine, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
Shimokawa
H
H
Eto
Y
Y
Hoshijima
M
M
Kaibuchi
K
K
Takeshita
A
A
D000818:Animals; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D003331:Coronary Vessels / Q000473:pathology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011859:Radiography; D013552:Swine; D014162:Transfection; D014661:Vasoconstriction / Q000502:physiology; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases