20-hydroxyeicosatetraenoic acid-induced vasoconstriction and inhibition of potassium current in cerebral vascular smooth muscle is dependent on activation of protein kinase C
20-hydroxyeicosatetraenoic acid-induced vasoconstriction and inhibition of potassium current in cerebral vascular smooth muscle is dependent on activation of protein kinase C
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DOI：
10.1074/jbc.272.43.27345
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发表时间：
1997-10-24
影响因子：
4.8
通讯作者：
Harder, D
中科院分区：
文献类型：
--
作者：
Lange, A;Gebremedhin, D;Harder, D
20-羟基二十碳四烯酸（20-HETE）是花生四烯酸的细胞色素P450代谢产物，是一种有效的血管收缩剂，并与肾动脉和脑动脉的肌源性激活有关。我们检测了蛋白激酶C（PKC）在20-HETE诱导猫脑血管平滑肌血管收缩和抑制全细胞K+电流的信号转导途径中的作用。20-HETE诱导了加压猫大脑中动脉的浓度依赖性收缩（1 μ M时为-29 +/-8%）。然而，在存在N-肉豆蔻酰化PKC假底物抑制剂肽（Myr Psi PKC-I（19-27））的情况下，20-HETE诱导浓度依赖性血管舒张（在1 μ M时为26 +/-4%）。在全细胞电压钳研究中，20-HETE的应用抑制了猫脑血管平滑肌细胞中记录的全细胞K+电流，Myr Psi PKC-I减弱了该作用（19-27）。PKC激活在响应20-HETE中的作用的进一步证据是发现20-HETE以浓度和PKC依赖性方式增加培养的猫脑血管平滑肌细胞中豆蔻酰化的富含丙氨酸的PKC底物的磷酸化。这些数据提供了证据表明，PKC是一个不可分割的一部分，通过该信号转导途径，20-HETE引起脑动脉血管收缩和抑制猫脑血管平滑肌的全细胞K+电流。
20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 metabolite of arachidonic acid, is a potent vasoconstrictor, and has been implicated in the myogenic activation of renal and cerebral arteries. We examined the role of protein kinase C (PKC) in the signal transduction pathway by which 20-HETE induces vasoconstriction and inhibition of whole-cell K+ current in cat cerebral vascular smooth muscle, 20-HETE induced a concentration-dependent constriction in isolated pressurized cat middle cerebral arteries (-29 +/- 8% at 1 mu M). However, in the presence of an N-myristoylated PKC pseudosubstrate inhibitor peptide (Myr Psi PKC-I(19-27)) 20-HETE induced a concentration-dependent vasodilation (26 +/- 4% at 1 mu M). In whole-cell voltage clamp studies, application of 20-HETE inhibited whole-cell K+ current recorded in cat cerebral vascular smooth muscle cells, an effect that was attenuated by Myr Psi PKC-I(19-27). Further evidence for the role of PKC activation in response to 20-HETE is the finding that 20-HETE increased the phosphorylation of myristoylated, alanine rich PKC substrate in cultured cat cerebral vascular smooth muscle cells in a concentration-and PKC-dependent manner. These data provide evidence that PKC is an integral part of the signal transduction pathway by which 20-HETE elicits vasoconstriction of cerebral arteries and inhibition of whole-cell K+ current in cat cerebral vascular smooth muscle.