Evidence for Protein Kinase C-Mediated Activation of Rho-Kinase in a Porcine Model of Coronary Artery Spasm

Tadashi Kandabashi, Hiroaki Shimokawa, Kenji Miyata, Ikuko Kunihiro, Yasuhiro Eto, Kunio Morishige, Yasuharu Matsumoto, Kazuo Obara, Koichi Nakayama, Shosuke Takahashi, Akira Takeshita

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)

Abstract

Objective-We have recently demonstrated that protein kinase C (PKC) and Rho-kinase play important roles in coronary vasospasm in a porcine model. However, it remains to be examined whether there is an interaction between the two molecules to cause the spasm. Methods and Results-A segment of left porcine coronary artery was chronically treated with IL-β-bound microbeads in vivo. Two weeks after the operation, phorbol ester caused coronary spasm in vivo and coronary hypercontractions in vitro at the IL-β-treated segment; both were significantly inhibited by hydroxyfasudil, a specific Rho-kinase inhibitor. Guanosine 5′-[γ-thio] triphosphate (GTPγS), which activates Rho with a resultant activation of Rho-kinase, enhanced Ca2+ sensitization of permeabilized vascular smooth muscle cells, which were resistant to the blockade of PKC by calphostin C. The GTPγS-induced Ca2+ sensitization was greater in the spastic segment than in the control segment. Western blot analysis revealed that only PKCδ isoform was activated during the hypercontraction. Conclusions-These results demonstrate that PKC and Rho-kinase coexist on the same intracellular signaling pathway, with PKC located upstream on Rho-kinase, and that among the PKC isoforms, only PKCδ may be involved. Thus, the strategy to inhibit Rho-kinase rather than PKC may be a more specific and useful treatment for coronary spasm.

Original languageEnglish
Pages (from-to)2209-2214
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume23
Issue number12
DOIs
Publication statusPublished - Dec 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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