Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells

Junko Hiroki, Hiroaki Shimokawa, Midoriko Higashi, Keiko Morikawa, Tadashi Kandabashi, Natsumi Kawamura, Toru Kubota, Toshihiro Ichiki, Mutsuki Amano, Kozo Kaibuchi, Akira Takeshita

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Abstract

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.

Original languageEnglish
Pages (from-to)537-546
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume37
Issue number2
DOIs
Publication statusPublished - Aug 2004

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Hiroki, J., Shimokawa, H., Higashi, M., Morikawa, K., Kandabashi, T., Kawamura, N., Kubota, T., Ichiki, T., Amano, M., Kaibuchi, K., & Takeshita, A. (2004). Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. Journal of Molecular and Cellular Cardiology, 37(2), 537-546. https://doi.org/10.1016/j.yjmcc.2004.05.008