TY - JOUR
T1 - Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells
AU - Hiroki, Junko
AU - Shimokawa, Hiroaki
AU - Higashi, Midoriko
AU - Morikawa, Keiko
AU - Kandabashi, Tadashi
AU - Kawamura, Natsumi
AU - Kubota, Toru
AU - Ichiki, Toshihiro
AU - Amano, Mutsuki
AU - Kaibuchi, Kozo
AU - Takeshita, Akira
N1 - Funding Information:
We thank M. Sonoda, M. Motoishi, and S. Masuda for excellent technical assistance. This study was supported in part by the grant for the 21st Century COE Program and the grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan (Nos. 10177223, 10357006, 12032215, 12470158, 12877114, 13307024, 13557068) and the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan.
PY - 2004/8
Y1 - 2004/8
N2 - 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-1β, 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 Iκ-B, suggesting an involvement of PKC and NF-κB 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-κB-/- 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-1β) in hcVSMC with an involvement of PKC and NF-κB both in vitro and in vivo.
AB - 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-1β, 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 Iκ-B, suggesting an involvement of PKC and NF-κB 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-κB-/- 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-1β) in hcVSMC with an involvement of PKC and NF-κB both in vitro and in vivo.
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U2 - 10.1016/j.yjmcc.2004.05.008
DO - 10.1016/j.yjmcc.2004.05.008
M3 - Article
C2 - 15276023
AN - SCOPUS:3242730347
SN - 0022-2828
VL - 37
SP - 537
EP - 546
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -