Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Clin Sci (Lond). 2013 Jun;124(12):695-700. doi: 10.1042/CS20120483.
20-HETE (20-hydroxyeicosatetraenoic acid), a vasoconstrictor metabolite of arachidonic acid formed through the action of CYP4A (cytochrome P450-4A) in vascular smooth muscle cells, has been implicated in the development of hypertension and vascular dysfunction. There have been a number of reports in human subjects demonstrating an association between elevated urinary excretion of 20-HETE and hypertension, as well as increased 20-HETE production and vascular dysfunction. The Dahl SS (salt-sensitive) rat is a genetic model of salt-sensitive hypertension that exhibits vascular dysfunction, even when maintained on a normal-salt diet and before the development of hypertension. This mini-review highlights our current research on the role of CYP4A and 20-HETE in the vascular dysfunction of the Dahl SS rat. In our studies, the SS rat is compared with the consomic SS-5BN rat, having chromosome 5 from the salt-resistant Brown Norway rat (carrying all CYP4A genes) introgressed on to the SS genetic background. Our laboratory has demonstrated restoration of normal vascular function in the SS rat with inhibition of the CYP4A/20-HETE pathway, suggesting a direct role for this pathway in the vascular dysfunction in this animal model. Our studies have also shown that the SS rat has an up-regulated CYP4A/20-HETE pathway within their cerebral vasculature compared with the SS-5BN consomic rat, which causes endothelial dysfunction through the production of ROS (reactive oxygen species). Our data shows that ROS influences the expression of the CYP4A/20-HETE pathway in the SS rat in a feed-forward mechanism whereby elevated ROS stimulates production of 20-HETE. The presence of this vicious cycle offers a possible explanation for the spiralling effects of elevated 20-HETE on the development of vascular dysfunction in this animal model.
20-HETE（20-羟二十碳四烯酸）是花生四烯酸的血管收缩代谢产物，通过血管平滑肌细胞中的 CYP4A（细胞色素 P450-4A）作用形成，与高血压和血管功能障碍的发展有关。有许多人类研究报告表明，20-HETE 尿排泄量升高与高血压以及 20-HETE 产生增加和血管功能障碍之间存在关联。Dahl SS（盐敏感）大鼠是一种盐敏感高血压的遗传模型，即使在正常盐饮食下并在高血压发生之前，也会表现出血管功能障碍。这篇小型综述强调了我们目前关于 CYP4A 和 20-HETE 在 Dahl SS 大鼠血管功能障碍中的作用的研究。在我们的研究中，将 SS 大鼠与 consomic SS-5BN 大鼠进行了比较，后者将来自盐抗性棕色挪威大鼠的第 5 号染色体（携带所有 CYP4A 基因）导入 SS 遗传背景。我们的实验室已经证明，通过抑制 CYP4A/20-HETE 途径，可以恢复 SS 大鼠的正常血管功能，这表明该途径在该动物模型中的血管功能障碍中具有直接作用。我们的研究还表明，与 consomic SS-5BN 大鼠相比，SS 大鼠的脑血管中 CYP4A/20-HETE 途径上调，这会通过产生 ROS（活性氧）导致内皮功能障碍。我们的数据表明，ROS 通过正反馈机制影响 SS 大鼠中 CYP4A/20-HETE 途径的表达，其中升高的 ROS 刺激 20-HETE 的产生。这种恶性循环的存在为升高的 20-HETE 对该动物模型中血管功能障碍发展的螺旋效应提供了可能的解释。
