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on October 30, 2003

Arteriosclerosis, Thrombosis, and Vascular Biology. 2003
Published online before print October 30, 2003, doi: 10.1161/01.ATV.0000104010.87348.26
A more recent version of this article appeared on December 1, 2003
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Submitted on August 24, 2003
Accepted on September 24, 2003

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 ; and Akira Takeshita

From the Department of Cardiovascular Medicine (T.K., H.S., K. Miyata, I.K., Y.E., K. Morishige, Y.M., A.T.) and the Department of Anesthesiology and Critical Care Medicine (T.K., S.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan and the Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (K.O., K.N.).

* To whom correspondence should be addressed. E-mail: shimo{at}cardiol.med.kyushu-u.ac.jp.

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-1{beta}-bound microbeads in vivo. Two weeks after the operation, phorbol ester caused coronary spasm in vivo and coronary hypercontractions in vitro at the IL-1{beta}-treated segment; both were significantly inhibited by hydroxyfasudil, a specific Rho-kinase inhibitor. Guanosine 5'-[{gamma}-thio]triphosphate (GTP{gamma}S), 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 GTP{gamma}S-induced Ca2+ sensitization was greater in the spastic segment than in the control segment. Western blot analysis revealed that only PKC{delta} 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 PKC{delta} may be involved. Thus, the strategy to inhibit Rho kinase rather than PKC may be a more specific and useful treatment for coronary spasm.
Key words: arteriosclerosis • coronary disease • smooth muscle • signal transduction




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