Arachidonic acid cytochrome P450 epoxygenase pathway

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. 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. Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators. Epoxidation can occur at any of the four double bonds of arachidonic acid, giving rise to four regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs are synthesized in the endothelium and activate large-conductance Ca2+-activated K+ channels (BKCa), causing hyperpolarization of the vascular smooth muscle and vasorelaxation. Thus, EETs function as an endothelium-derived hyperpolarizing factor (EDHF) in a number of vascular beds, including the coronary and renal circulations, producing a decrease in blood pressure. Soluble epoxide hydrolase (sEH), which converts EETs to dihydroxyeicosatrienoic acids (DHETs), attenuates many of the functional effects of EETs. These seminal findings have been described in a number of detailed reviews (1Campbell W.B. Harder D.R. Endothelium derived hyperpolarizing factors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone.Circ. Res. 1999; 84: 484-488Crossref PubMed Cytochrome P450 and arachidonic acid and functional of arachidonic acid Res. PubMed metabolites of arachidonic acid in the of PubMed of epoxyeicosatrienoic acids on PubMed with and that EETs have beneficial effects on the vascular and and many are at actions W.B. acid metabolites as endothelium-derived hyperpolarizing PubMed endothelium-derived hyperpolarizing factor (EDHF) to epoxyeicosatrienoic acids and PubMed W.B. for epoxyeicosatrienoic acids in the PubMed of epoxyeicosatrienoic acids in myocardium PubMed cytochrome and PubMed is on sEH inhibition as a for increasing the beneficial effects of EETs hydrolase and metabolites as for renal PubMed epoxide hydrolase as a for PubMed are synthesized by that CYP in on arachidonic acid cytosolic is Epoxyeicosatrienoic acids and Res. PubMed an on a to of the double bonds of arachidonic acid, and the double is as the epoxide CYP regioisomers, with Thus, epoxygenases that produce 14,15-EET also produce a of and a of in Cytochrome P450 and arachidonic acid and functional of arachidonic acid Res. PubMed of epoxyeicosatrienoic acids on PubMed Because the have a number of and functional EETs are as a of is an and are and in the actions of the of epoxyeicosatrienoic acids on PubMed 14,15-EET is the for sEH of epoxyeicosatrienoic acids on PubMed and is the that K+ channels in the renal acid channels in the cytochrome PubMed are taken up by many of of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed and and acid binding proteins bind EETs acid binding proteins of epoxyeicosatrienoic acids by epoxide PubMed that may EET the membrane and into the as as EET into and to sEH for of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed Because to attenuates many of the actions of EETs, binding to may the intracellular of EETs and functional in the that EETs also have the to EETs into and convert to that in the and they can be to derivatives that are incorporated into coronary convert to a PubMed in the of EETs to sEH is of epoxyeicosatrienoic acid in for the vascular effects of epoxide hydrolase PubMed of 14,15-EET, which is an epoxide of acid, coronary by hyperpolarizing smooth muscle in a to EETs W.B. of acid to acids by coronary PubMed inhibition EET of EET to by sEH is the of EET attenuates functional effects of EETs, sEH a for increasing and prolonging the actions of EETs. sEH inhibition and to intracellular EET in EET into and by including and are of the of intracellular EET and EET is intracellular are the intracellular of produce autacrine and paracrine actions are in CYP epoxygenases are in and are is formed W.B. cytochrome interaction endothelium-derived hyperpolarizing Res. 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PubMed acid binding proteins of epoxyeicosatrienoic acids by epoxide PubMed anti-inflammatory of the of epoxyeicosatrienoic and epoxide PubMed functional of EET into is EETs are incorporated into the of the phospholipids, and that a of the is is to the of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed that EET may the of membrane and the function of proteins in the of EETs may signal transduction systems. EETs also are the by a mechanism Epoxyeicosatrienoic acids and Res. PubMed of epoxyeicosatrienoic acid in for the vascular effects of epoxide hydrolase PubMed EETs in may an intracellular that is for the is Epoxyeicosatrienoic acids and Res. PubMed is that containing EET are for the of lipid mediators. and produce that 14,15-EET of cytochrome metabolites with for are endocannabinoids that activate and receptors, and of renal by causing the of that activate the factor receptor and mechanism of a cytochrome PubMed In addition, containing EET are the for the synthesized in the and by and cytochrome to and epoxyeicosatrienoic acid PubMed EET into may to the intracellular EET and be of the mechanism that functional of the EET the the EET can be by sEH functional effects of EETs have been to occur through a number of signal transduction of epoxyeicosatrienoic acids on PubMed that the in the coronary functions through a that activates vascular smooth muscle paracrine mechanism the and an in W.B. acid metabolites as endothelium-derived hyperpolarizing PubMed of an in and of renal receptor of is by EETs that activate the PubMed a mechanism the in and of metabolites of arachidonic acid in and PubMed the relaxation of renal also is by of the in this an in to and Ca2+-activated K+ PubMed of channels is an mechanism for the coronary Epoxyeicosatrienoic acids and hyperpolarization in PubMed and K+ and the endothelium relaxation of the vascular smooth have anti-inflammatory and actions in the endothelium W.B. for epoxyeicosatrienoic acids in the PubMed anti-inflammatory by through a that effects of cytochrome P450 PubMed and 14,15-EET this through of a that Cytochrome P450 epoxygenases protect by factor and PubMed effects of EETs also have been in the hydrolase and metabolites as for renal PubMed have been in the of EETs of epoxyeicosatrienoic acids on PubMed endothelium-derived hyperpolarizing factor (EDHF) to epoxyeicosatrienoic acids and PubMed been to by activating an Cytochrome P450 is on PubMed that functions by activating of of and by epoxyeicosatrienoic Res. PubMed are to produce to and been in is a of in PubMed of which to the been in with 14,15-EET for in and PubMed and 14,15-EET have effects of ischemic and they decrease of epoxyeicosatrienoic acids in myocardium PubMed W.B. of the EET on by EETs in PubMed have been to the including of channels by to of binding to the of by epoxyeicosatrienoic PubMed of channels by a of by which epoxyeicosatrienoic acids in PubMed and of a of are by epoxyeicosatrienoic acids to protect PubMed are synthesized in the by through a mechanism to and and are in Harder D.R. of epoxyeicosatrienoic receptors, and in in PubMed They also produce by activating and that with and Harder D.R. by acid is by the of and in the PubMed In addition, EETs and in Soluble epoxide a in PubMed of sEH is beneficial and the functional effects of EETs of epoxyeicosatrienoic acid in for the vascular effects of epoxide hydrolase PubMed in EET in the the to is EET for into and for interaction with ion and function of been of epoxyeicosatrienoic acids on PubMed and the is that sEH inhibition is However, some is by the findings that activates channels in coronary and coronary acids are of Ca2+-activated K+ channels in coronary PubMed in a acid activates receptor PubMed any of effects are to as epoxide hydrolase as a for PubMed that they also and of by epoxide hydrolase PubMed decrease vascular smooth muscle of smooth muscle by acids receptor of PubMed renal metabolites of arachidonic acid in the of PubMed and decrease renal hydrolase and metabolites as for renal PubMed renal epoxyeicosatrienoic acid attenuates renal function and in PubMed is with the that sEH through a EET epoxide hydrolase in vascular in and in PubMed sEH with and have been with are of epoxide hydrolase with PubMed and for are EET acid the epoxide synthesized eicosapentaenoic acid, Cytochrome eicosapentaenoic acid metabolites are PubMed mechanism of with the the acid the in PubMed that some beneficial effects of acid may be to of eicosapentaenoic acid to synthesized epoxide derivatives of acid are of coronary Cytochrome metabolites of coronary by activating large-conductance PubMed the of derivatives been in are as autacrine and paracrine lipid mediators. the on the and of that EETs have effects on ion channels and signal transduction pathways. EETs also are incorporated into and angiogenesis, and EET and sEH and CYP and sEH are to and functional effects of EETs. of EET and endocannabinoids up and In addition, many for are by in that EETs have anti-inflammatory effects in the and kidney, produce and protect the myocardium and ischemic Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators. Epoxidation can occur at any of the four double bonds of arachidonic acid, giving rise to four regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs are synthesized in the endothelium and activate large-conductance Ca2+-activated K+ channels (BKCa), causing hyperpolarization of the vascular smooth muscle and vasorelaxation. Thus, EETs function as an endothelium-derived hyperpolarizing factor (EDHF) in a number of vascular beds, including the coronary and renal circulations, producing a decrease in blood pressure. Soluble epoxide hydrolase (sEH), which converts EETs to dihydroxyeicosatrienoic acids (DHETs), attenuates many of the functional effects of EETs. These seminal findings have been described in a number of detailed reviews (1Campbell W.B. Harder D.R. Endothelium derived hyperpolarizing factors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone.Circ. Res. 1999; 84: 484-488Crossref PubMed Cytochrome P450 and arachidonic acid and functional of arachidonic acid Res. PubMed metabolites of arachidonic acid in the of PubMed of epoxyeicosatrienoic acids on PubMed with and that EETs have beneficial effects on the vascular and and many are at actions W.B. acid metabolites as endothelium-derived hyperpolarizing PubMed endothelium-derived hyperpolarizing factor (EDHF) to epoxyeicosatrienoic acids and PubMed W.B. for epoxyeicosatrienoic acids in the PubMed of epoxyeicosatrienoic acids in myocardium PubMed cytochrome and PubMed is on sEH inhibition as a for increasing the beneficial effects of EETs hydrolase and metabolites as for renal PubMed epoxide hydrolase as a for PubMed EET are synthesized by that CYP in on arachidonic acid cytosolic is Epoxyeicosatrienoic acids and Res. PubMed an on a to of the double bonds of arachidonic acid, and the double is as the epoxide CYP regioisomers, with Thus, epoxygenases that produce 14,15-EET also produce a of and a of in Cytochrome P450 and arachidonic acid and functional of arachidonic acid Res. PubMed of epoxyeicosatrienoic acids on PubMed Because the have a number of and functional EETs are as a of is an and are and in the actions of the of epoxyeicosatrienoic acids on PubMed 14,15-EET is the for sEH of epoxyeicosatrienoic acids on PubMed and is the that K+ channels in the renal acid channels in the cytochrome PubMed are taken up by many of of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed and and acid binding proteins bind EETs acid binding proteins of epoxyeicosatrienoic acids by epoxide PubMed that may EET the membrane and into the as as EET into and to sEH for of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed Because to attenuates many of the actions of EETs, binding to may the intracellular of EETs and functional in the that EETs also have the to EETs into and convert to that in the and they can be to derivatives that are incorporated into coronary convert to a PubMed in the of EETs to sEH is of epoxyeicosatrienoic acid in for the vascular effects of epoxide hydrolase PubMed of 14,15-EET, which is an epoxide of acid, coronary by hyperpolarizing smooth muscle in a to EETs W.B. of acid to acids by coronary PubMed produce autacrine and paracrine actions are in CYP epoxygenases are in and are is formed W.B. cytochrome interaction endothelium-derived hyperpolarizing Res. PubMed paracrine effects are by the EET into the the effects also are by the EET into the the that they intracellular actions of EET that is in the be EETs are synthesized by that CYP in on arachidonic acid cytosolic is Epoxyeicosatrienoic acids and Res. PubMed an on a to of the double bonds of arachidonic acid, and the double is as the epoxide CYP regioisomers, with Thus, epoxygenases that produce 14,15-EET also produce a of and a of in Cytochrome P450 and arachidonic acid and functional of arachidonic acid Res. PubMed of epoxyeicosatrienoic acids on PubMed Because the have a number of and functional EETs are as a of is an and are and in the actions of the of epoxyeicosatrienoic acids on PubMed 14,15-EET is the for sEH of epoxyeicosatrienoic acids on PubMed and is the that K+ channels in the renal acid channels in the cytochrome PubMed EETs are taken up by many of of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed and and acid binding proteins bind EETs acid binding proteins of epoxyeicosatrienoic acids by epoxide PubMed that may EET the membrane and into the as as EET into and to sEH for of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed Because to attenuates many of the actions of EETs, binding to may the intracellular of EETs and functional in the that EETs also have the to EETs into and convert to EETs that in the and they can be to derivatives that are incorporated into coronary convert to a PubMed in the of EETs to sEH is of epoxyeicosatrienoic acid in for the vascular effects of epoxide hydrolase PubMed of 14,15-EET, which is an epoxide of acid, coronary by hyperpolarizing smooth muscle in a to EETs W.B. of acid to acids by coronary PubMed EETs produce autacrine and paracrine actions are in CYP epoxygenases are in and are is formed W.B. cytochrome interaction endothelium-derived hyperpolarizing Res. PubMed paracrine effects are by the EET into the the effects also are by the EET into the the that they intracellular actions of EET that is in the be have been to the actions of EETs of epoxyeicosatrienoic acids on PubMed EET binding to receptors, and the is an intracellular of and functional the that EETs bind to a EET receptor that is by a to intracellular signal transduction of epoxyeicosatrienoic acids on PubMed W.B. of epoxyeicosatrienoic acid binding in a PubMed However, this to the EET receptor been mechanism EET binding to for that also function by to intracellular pathways. an intracellular is on the that EETs have many of mechanism of the EET by the with the EET with ion for an intracellular mechanism of the that EETs are incorporated into and bind to and receptor of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. PubMed acid binding proteins of epoxyeicosatrienoic acids by epoxide PubMed anti-inflammatory of the of epoxyeicosatrienoic and epoxide PubMed have been to the actions of EETs of epoxyeicosatrienoic acids on PubMed EET binding to receptors, and the is an intracellular of and functional the that EETs bind to a EET receptor that is by a to intracellular signal transduction of epoxyeicosatrienoic acids on PubMed W.B. of epoxyeicosatrienoic acid binding in a PubMed However, this to the EET receptor been mechanism EET binding to for that also function by to intracellular pathways. an intracellular is on the that EETs have many of mechanism of the EET by the with the EET with ion for an intracellular mechanism of the that EETs are incorporated into and bind to and receptor of epoxyeicosatrienoic acids on PubMed Epoxyeicosatrienoic acids and Res. 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EETs also are incorporated into and angiogenesis, and EET and sEH and CYP and sEH are to and functional effects of EETs. of EET and endocannabinoids up and In addition, many for are by in that EETs have anti-inflammatory effects in the and kidney, produce and protect the myocardium and ischemic EETs are as autacrine and paracrine lipid mediators. the on the and of that EETs have effects on ion channels and signal transduction pathways. EETs also are incorporated into and angiogenesis, and EET and sEH and CYP and sEH are to and functional effects of EETs. of EET and endocannabinoids up and In addition, many for are by in that EETs have anti-inflammatory effects in the and kidney, produce and protect the myocardium and ischemic