1996 Fiscal Year Final Research Report Summary
Role of protein tyrosine kinase in functional changes of hyperplastic arteries
| Project/Area Number |
07660404
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Basic veterinary science/Basic zootechnical science
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| Research Institution | Miyazaki University |
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Principal Investigator |
ITO Katsuaki Miyazaki University, Faculty of Agriculture, Professor, 農学部, 教授 (70136795)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAI Masaaki Miyazaki University, Faculty of Agriculture, Assistant Professor, 農学部, 助手 (00217647)
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| Project Period (FY) |
1995 – 1996
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| Keywords | Hyperplastic artery / Endothelium injury / Tyrosine kinase / Protein kinase C / Cellular calcium mobilization / Calcium sensitivity / Hypertensive vessels / Monocrotaline |
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| Research Abstract |
We investigated how protein kinases were involved in functional changes in two kinds of experimentally made hyperplastic arteries. Vascular angioplasty was performed by rubbing the endothelial layr of rabbit carotid artery with a balloon catheter. At 6 weeks of surgery, marked hyperplasia in the intimal layr of the artery was observed. Myosin light chain (MLC) phosphorylation and the contractile response to prostaglandin F2alpha (PGF2alpha) were enhanced in the artery, although the cytosolic Ca^<2+> mobilization was similar to control artery. While serine/threonine kinase inhibitors inhibited the MLC phosphorylation and the contraction in hyperplastic artery than in normal one, tyrosine kinase inhibitors equally inhibited the contraction in both arteries, suggesting that tyrosine kinase was not responsible for the hypercontraction. In a separate experiment, rats were subcutaneously given monocrotaline, which impaired the endothelium of pulmonary artery, resulting in pulmonary hypertens
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ion. Monocrotaline-affected artery showed a marked hyperplasty in the medial layr. In this artery, the relaxing action of the endothelium was markedly impaired. The artery also produced an active tension at the resting state. This active tension was probably due to the membrane depolarization and increased cytosolic Ca^<2+>. The endothelium of the artery seemed to work to increase the resting tension. At some stage, the contractile response to PGF2alpha was enhanced. In this case, tyrosine kinase inhibitors exerted more potent inhibition on the contraction than in the control artery. Thus, tyrosine kinase may be responsible for the abnormal contractility in this type of vascular disease.
In addition to the above study we evaluated the selectivity of several protein kinase inhibitors and found that a tyrosine kinase may be involved in PGF2alpha-induced activation of voltage-dependent Ca^<2+> channels in rabbit aorta. We also investigated the mechanism of protein kinase C (PKC)-dependent Ca^<2+> sensitization of contraction. It was suggested that PKC activation and the subsequent release of arachidonic acid inhibit MLC phosphatase, increasing the level of MLC phosphorylation. Tyrosine kinase does not seem to be present in the down-stream of PKC activation. Less
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