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 cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominant-negative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1beta, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of beta-galactosidase, into the interleukin-1beta-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation 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-kinase is substantially involved in coronary constrictive remodeling and vasospastic responses, both of which can be reversed by the 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
Kandabashi
T
T
Miyata
K
K
Matsumoto
Y
Y
Hoshijima
M
M
Kaibuchi
K
K
Takeshita
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D015153:Blotting, Western; D003327:Coronary Disease / Q000235:genetics / Q000628:therapy*; D003329:Coronary Vasospasm / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007375:Interleukin-1 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000494:pharmacology; D008840:Microfilament Proteins / Q000494:pharmacology; D010750:Phosphoproteins / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics; D054460:rho-Associated Kinases; D000099149:Ezrin
D001798:Blood Proteins; D003598:Cytoskeletal Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012701:Serotonin; D001616:beta-Galactosidase; D054460:rho-Associated Kinases; D000099149:Ezrin; C071058:moesin; C071776:radixin