Role of protein tyrosine kinase in functional changes of hyperplastic arteries

我们研究了蛋白激酶是如何参与两种实验性增生性动脉的功能变化的。血管成形术采用球囊导管摩擦兔颈动脉内皮层的方法。术后6周，动脉内膜明显增生。肌球蛋白轻链(MLC)的磷酸化和对前列腺素F2α(PGF2α)的收缩反应在动脉中得到增强，尽管胞浆Ca~(2+)动员与对照动脉相似。当丝氨酸/苏氨酸激酶抑制剂抑制MLC的磷酸化和收缩时，酪氨酸激酶抑制剂同样抑制两条动脉的收缩，提示酪氨酸激酶不是导致血管过度收缩的原因。在另一项实验中，大鼠皮下注射野百合碱，它损害了肺动脉内皮细胞，导致肺高压…。更多的离子。野百合碱影响的动脉内侧层有明显的肥大。在这条动脉中，内皮的松弛作用明显受损。在静息状态下，动脉也产生主动张力。这种主动张力可能是由于膜去极化和胞内Ca~(2+)&Gt；升高所致。动脉内皮细胞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，酪氨酸激酶可能与这类血管疾病的异常收缩有关。除了上述研究，我们还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参与了PGF2pha诱导的兔主动脉电压依赖性钙通道的激活。我们还研究了蛋白激酶C(PKC)依赖的钙敏感性收缩的机制。提示PKC的激活和随后花生四烯酸的释放抑制了MLC磷酸酶，增加了MLC的磷酸化水平。酪氨酸激酶似乎不存在于PKC激活的下游。较少

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