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Titolo:
Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm
Autore:
Shimokawa, H; Seto, M; Katsumata, N; Amano, M; Kozai, T; Yamawaki, T; Kuwata, K; Kandabashi, T; Egashira, K; Ikegaki, I; Asano, T; Kaibuchi, K; Takeshita, A;
Indirizzi:
Kyushu Univ, Sch Med, Angiocardiol Res Inst, Higashi Ku, Fukuoka 8128582, Japan Kyushu Univ Fukuoka Japan 8128582 st, Higashi Ku, Fukuoka 8128582, Japan Kyushu Univ, Sch Med, Cardiovasc Clin, Higashi Ku, Fukuoka 8128582, Japan Kyushu Univ Fukuoka Japan 8128582 in, Higashi Ku, Fukuoka 8128582, Japan Asahi Chem Ind Co Ltd, Life Sci Ctr, Shizuoka 4102321, Japan Asahi Chem Ind Co Ltd Shizuoka Japan 4102321 tr, Shizuoka 4102321, Japan Nara Inst Sci & Technol, Div Signal Transduct, Ikoma 6300101, Japan Nara Inst Sci & Technol Ikoma Japan 6300101 nsduct, Ikoma 6300101, Japan
Titolo Testata:
CARDIOVASCULAR RESEARCH
fascicolo: 4, volume: 43, anno: 1999,
pagine: 1029 - 1039
SICI:
0008-6363(199909)43:4<1029:RPIEML>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
SMOOTH-MUSCLE MYOSIN; PIGS IN-VIVO; PROTEIN-KINASE; VASOSPASTIC RESPONSES; PHOSPHATASE; INTERLEUKIN-1-BETA; ACTIVATION; INHIBITION; HA1077; SENSITIZATION;
Keywords:
coronary vasospasm; Rho-kinase; myosin light chain; calcium;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Shimokawa, H Kyushu Univ, Sch Med, Angiocardiol Res Inst, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan Kyushu Univ 3-1-1 Maidashi Fukuoka Japan 8128582 8582, Japan
Citazione:
H. Shimokawa et al., "Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm", CARDIO RES, 43(4), 1999, pp. 1029-1039

Abstract

Objective: We recently demonstrated in our swine model of coronary artery spasm that enhanced myosin light chain (MLC) phosphorylations (both MLC mono- and diphosphorylations) play a central role in the pathogenesis of the spasm. However, the molecular mechanism for and the phosphorylation sites for the enhanced MLC phosphorylations were unknown. In the present study, we addressed these points using hydroxyfasudil, a novel inhibitor of protein kinases, which we found preferentially inhibits Rho-kinase. Methods: The specificity of the inhibitory effects of hydroxyfasudil on Rho-kinase, MLCK, MRCK beta and PKC were examined by kinase assay in vitro. The left porcine coronary artery was chronically treated with interleukin-1 beta (IL-1 beta, 2.5 mu g). Two weeks after the operation, coronary artery vasomotion was examined both in vivo and in vitro. MLC phosphorylations were examined by Western blot analysis and the sites for the phosphorylations by anti-phosphorylated MLC antibodies that identified the monophosphorylation site as Ser19 and diphophorylation sites as Ser19/Thr18 of MLC. Results: Inhibitory effects of hydroxyfasudil was at least 100 times more potent for Rho-kinase as compared with other protein kinases tested. Intracoronary serotonin (10 mu g/kg) caused coronary hyperconstriction at the IL-1 beta-treated site in vivo, which was dose-dependently inhibited by hydroxyfasudil (p<0.01). The coronary segment taken from the spastic site also showed hypercontractions to serotonin in vitro, which were again dose-dependently inhibited by hydroxyfasudil (p<0.01). Western blot analysis showed that MLC monophosphorylation was significantly greater in the spastic segment than in the control segment, while MLC diphosphorylation was noted only at the spastic segment (p<0.01). The sites for the mono- and diphosphorylated MLC were identified as themonophosphorylated site Ser19 and diphosphorylated sites Ser19/Thr18 of MLC, respectively. Both types of MLC phosphorylations at the spastic segment were markedly inhibited by hydroxyfasudil (p<0.01). Conclusion: These results indicate that hydroxyfasudil sensitive Rho-kinase-mediated pathway appears to mediate the enhanced MLC phosphorylations (on Ser19 and Ser19/Thr18 residues) and plays a central role in the pathogenesis of coronary artery spasm. (C) 1999 Elsevier Science B.V. All rights reserved.

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Documento generato il 26/09/20 alle ore 08:31:56