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Review
. 2016:77:105-41.
doi: 10.1016/bs.apha.2016.04.003. Epub 2016 May 5.

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

J D Imig  1
Affiliations
Review

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

J D Imig. Adv Pharmacol. 2016.

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.

Keywords: Angiogenesis; Atherosclerosis; Cytochrome P450; Eicosanoids; Endothelial-hyperpolarizing factor; Hypertension; Inflammation; Myogenic response; Soluble epoxide hydrolase.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

Dr. Imig has patents that cover the composition of matter for EET analogs. There are no other conflicts of interest, financial, or otherwise, declared by the author.

Figures

Fig. 1
Fig. 1
Diagram depicting pathways of cytochrome P450 (CYP) arachidonic metabolism. CYP 4A and CYP4F enzymes can generate 20-hydroxyeicosatraenoic acid (20-HETE). CYP2C and CYP2C enzymes generate epoxyeicosatrienoic acids (EETs). Soluble epoxide hydrolase (sEH) can hydrate EETs to form dihydroxyeicosatrienoic acids (DHETEs).
Fig. 2
Fig. 2
Diagram depicting 20-hydroxyeicosatraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) cell signaling mechanisms on vascular tone. 20-HETE inhibits large-conductance K+ channels and activates L-type Ca2+ channels leading to an increase in vascular smooth muscle intracellular Ca2+ and subsequent vasoconstriction. Endothelial-derived EETs activate vascular smooth muscle cell large-conductance K+ channels resulting in hyperpolarization and vasorelaxation.
Fig. 3
Fig. 3
Diagram depicting 20-hydroxyeicosatraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on angiogenesis. Angiogenesis is a biological activity where 20-HETE and EETs act in the same manner. EETs promote angiogenesis through mitogen-activated protein kinase (MAPK) activation and nuclear cyclin D1 generation, sphingosine kinase-1 (SK-1), and phosphatidylinositol 3-kinase (PI3K)/Akt pathways to activate transcription factors and the generation of cell cycle modulators, and protein kinase A (PKA) acting via the cAMP/PKA response element-binding protein (CREBP) resulting in COX-2 production that influences angiogenesis. 20-HETE promotes angiogenesis through vascular endothelial growth factor (VEGF) activation of MAPK/extracellular signaling-regulated (ERK) kinase (MEK) to increase the nuclear factor kappa-light-chain enhancer of activated B cells (NF-кB) and through NADPH oxidase (NOX) and PI3K/Akt pathways.
Fig. 4
Fig. 4
Diagram depicting 20-hydroxyeicosatraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) interactions on endothelial dysfunction. Vascular smooth muscle cell-derived 20-HETE acts on the endothelial cell to decrease nitric oxide (NO), increase angiotensin type 1 receptor (AT1R), and increase angiotensin-converting enzyme (ACE) to generate angiotensin II (ANG II). Increased ANG II and decreased NO will act to promote endothelial dysfunction. On the other hand, bradykinin stimulates endothelial cell EET generation that acts to interfere with ANG II actions on the AT1R and will oppose decreased NO levels resulting in improved endothelial function.
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