Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function.

Abstract

Endothelial and vascular smooth cells generate cytochrome P450 (CYP) arachidonic acid metabolites that can impact endothelial cell function and vascular homeostasis. The objective of this review is to focus on the physiology and pharmacology of endothelial CYP metabolites. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP hydroxylases. Advances in CYP enzymes, EETs, and 20-HETE by pharmacological and genetic means have led to a more complete understanding of how these eicosanoids impact on endothelial cell function. Endothelial-derived EETs were initially described as endothelial-derived hyperpolarizing factors. It is now well recognized that EETs importantly contribute to numerous endothelial cell functions. On the other hand, 20-HETE is the predominant CYP hydroxylase synthesized by vascular smooth muscle cells. Like EETs, 20-HETE acts on endothelial cells and impacts importantly on endothelial and vascular function. An important aspect for EETs and 20-HETE endothelial actions is their interactions with hormonal and paracrine factors. These include interactions with the renin-angiotensin system, adrenergic system, puringeric system, and endothelin. Alterations in CYP enzymes, 20-HETE, or EETs contribute to endothelial dysfunction and cardiovascular diseases such as ischemic injury, hypertension, and atherosclerosis. Recent advances have led to the development of potential therapeutics that target CYP enzymes, 20-HETE, or EETs. Thus, future investigation is required to obtain a more complete understanding of how CYP enzymes, 20-HETE, and EETs regulate endothelial cell function.