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。血管成形术是通过用气球导管摩擦兔颈动脉的内皮外线来进行的。在手术的6周时，观察到动脉内膜层中明显的增生。肌球蛋白轻链（MLC）磷酸化和对前列腺素F2alpha（PGF2Alpha）的收缩反应增强了，尽管胞质Ca^<2+>动员与对照艺术相似。丝氨酸/苏氨酸激酶抑制剂抑制了MLC磷酸化和增生艺术的收缩，而酪氨酸激酶抑制剂也同样抑制了这两种动脉的收缩，这表明酪氨酸激酶不负责超级触发。在另一项实验中，皮下给大鼠单蛋白，从而损害了肺动脉honterother的，导致肺高血压……更多的离子。受单激素影响的动脉在培养基中显示出明显的增生术。在此动脉中，内皮的放松作用显着损害。动脉还在静止状态产生了主动张力。这种主动张力可能是由于膜去极化和胞质Ca^<2+>增加所致。动脉的内皮似乎可以增加静止张力。在某个阶段，对PGF2alpha的收缩反应得到了增强。在这种情况下，酪氨酸激酶抑制剂对收缩的潜在抑制作用比对照动脉更有潜在的抑制作用。这就是酪氨酸激酶可能负责这种类型的血管疾病中的异常收缩率。在上述研究中，我们评估了几种蛋白激酶抑制剂的选择性，发现酪氨酸激酶可能与PGF2Alpha诱导的电压相关CA^<2+> CANELEL的激活涉及Rabbit Aorta中的CA^<2+>通道。我们还研究了蛋白激酶C（PKC）依赖性CA^<2+>的机理。据建议，PKC激活和随后的蛛网膜酸抑制MLC磷酸酶，从而增加了MLC磷酸化水平。酪氨酸激酶似乎不存在于PKC激活的下游。较少的