Abstract
Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca2+-activated K+ channels (BKCa). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactive epoxy-derivatives, and endocannabinoids containing 11,12- and 14,15-EET are formed. Many EET actions appear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellular signal transduction pathways. However, EETs also are taken up by cells, are incorporated into phospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions may occur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of the functional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolonging the beneficial actions of EETs.
Highlights
Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6, 8,9, 11,12, and 14,15-EET, that function as autacrine and paracrine mediators
Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators
EETs are synthesized in the endothelium and activate large-conductance Ca21-activated K1 channels (BKCa), causing hyperpolarization of the vascular smooth muscle and vasorelaxation
Summary
Three mechanisms have been proposed to explain the cellular actions of EETs [4]. Two involve EET binding to cell-surface receptors, and the other is an intracellular mechanism. A substantial amount of chemical and functional data supports the likelihood that EETs bind to a selective EET receptor that is coupled by a G-protein to intracellular signal transduction pathways [4, 19]. This possibility remains open to question because the putative EET receptor has not yet been identified or cloned. The third possibility, an intracellular mechanism, is based on the fact that EETs have many characteristics of long-chain fatty acids This mechanism involves uptake of the EET by the cell, with the cell-associated EET directly interacting with ion channels, signaling proteins, or transcription factors. EET metabolism and function S53 that EETs are incorporated into cell phospholipids and bind to cytoplasmic FABPs and peroxisome proliferator-activated receptor (PPAR)g [4, 12, 14, 20]
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