Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells.
Recent studies have demonstrated that upregulated Rho-kinase plays an important role in the pathogenesis of arteriosclerosis and vasospasm in both animals and humans. However, little is known about the molecular mechanism(s) involved in the Rho-kinase upregulation. Since inflammatory mechanisms have been implicated in the pathogenesis of arteriosclerosis and vasospasm, we examined whether inflammatory stimuli upregulate Rho-kinase in vitro and in vivo. In cultured human coronary vascular smooth muscle cells (hcVSMC), inflammatory stimuli, such as angiotensin II and interleukin-1beta, increased Rho-kinase expression (at both mRNA and protein levels) and function (as evaluated by the extent of the phosphorylation of the ERM (the ezrin/radixin/moesin) family, substrates of Rho-kinase) in a time- and concentration-dependent manner. The expression of Rho-kinase was inhibited by blockades of protein kinase C (PKC) (by either GF109253 or prolonged treatment with phorbol myristate acetate for 24 h) and an adenovirus-mediated gene transfer of dominant-active Ikappa-B, suggesting an involvement of PKC and NF-kappaB in the intracellular signal transduction pathway for the Rho-kinase expression. Furthermore, coronary vascular lesion formation (characterized by medial thickening and perivascular fibrosis) induced by a long-term administration of angiotensin II was markedly suppressed in NF-kappaB(-/-) mice with reduced expression and activity of Rho-kinase in vivo. These results indicate that the expression and function of Rho-kinase are upregulated by inflammatory stimuli (e.g. angiotensin II and IL-1beta) in hcVSMC with an involvement of PKC and NF-kappaB both in vitro and in vivo.
Department of Cardiovascular Medicine, and the 21st Century COE Program on Lifestyle-Related Diseases, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maldashi, Higashi-ku, Fukuoka 812-8582, Japan.
Junko
J
Hiroki
Hiroaki
H
Shimokawa
Midoriko
M
Higashi
Keiko
K
Morikawa
Tadashi
T
Kandabashi
Natsumi
N
Kawamura
Toru
T
Kubota
Toshihiro
T
Ichiki
Mutsuki
M
Amano
Kozo
K
Kaibuchi
Akira
A
Takeshita
D000804:Angiotensin II / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation; D054460:rho-Associated Kinases
D018836:Inflammation Mediators; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate