Role of protein tyrosine kinase in functional changes of hyperplastic arteries

蛋白酪氨酸激酶在增生性动脉功能变化中的作用

基本信息

批准号：
07660404
负责人：
ITO Katsuaki
金额：
$ 1.41万
依托单位：
Miyazaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

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 … More 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

我们研究了蛋白激酶如何参与两种实验性增生动脉的功能变化。通过用球囊导管摩擦兔颈动脉的内皮层进行血管成形术，在手术后 6 周，血管内膜层出现明显增生。观察到动脉肌球蛋白轻链 (MLC) 磷酸化和对前列腺素 F2α (PGF2α) 的收缩反应增强，尽管胞质Ca^2+动员与对照动脉相似，而丝氨酸/苏氨酸激酶抑制剂比正常动脉更能抑制MLC磷酸化和收缩，而酪氨酸激酶抑制剂同样抑制两条动脉的收缩。酪氨酸激酶并不是导致过度收缩的原因。在另一项实验中，大鼠皮下注射野百合碱，这会损害肺动脉内皮，导致肺动脉高压……受野百合碱影响的动脉在该动脉中显示出明显的增生，该动脉在静息状态下也产生了主动张力。膜去极化和增加的胞质Ca 2+ 动脉内皮似乎起到增加静息张力的作用，在某些阶段，对PGF2α的收缩反应增强。在这种情况下，酪氨酸激酶抑制剂对收缩的抑制作用比对照动脉更强，因此，酪氨酸激酶可能是导致此类血管疾病的异常收缩的原因。除了上述研究之外，我们还评估了几种药物的选择性。我们还研究了蛋白激酶C（PKC）依赖性的机制。 Ca ^ 2+ 收缩敏化表明PKC激活和随后的花生四烯酸的释放抑制MLC磷酸酶，增加MLC酪氨酸激酶的水平似乎不存在于PKC激活的下游。。较少的