Cytochrome P450 and arachidonic acid metabolites: role in myocardial ischemia/reperfusion injury revisited.
Ischemia-reperfusion of the heart and other organs results in the accumulation of unesterified arachidonic acid (AA) via the action of membrane-bound phospholipases, primarily phospholipase A2. AA can be metabolized by the classical cyclooxygenase (COX) and lipoxygenase (LOX) pathways to well-characterized metabolites and their respective cardioprotective end products such as prostacyclin (PGI2) and 12-hydroxyeicosatetraenoic acid (12-HETE). However, it has only been recently recognized that another less well-characterized pathway of AA metabolism, the cytochrome P450 (CYP) pathway, may have important cardiovascular effects. Several lines of data support the possibility that certain CYP metabolites resulting from the hydroxylation of AA such as 20-hydroxyeicosatetraenoic acid (20-HETE) are potent vasoconstrictors and may produce detrimental effects in the heart during ischemia and pro-inflammatory effects during reperfusion. On the other hand, a group of regioisomers resulting from the epoxidation of AA, including 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acid (EETs), have been shown to reduce ischemic and/or reperfusion injury in the heart and vasculature. This review will discuss the detrimental and beneficial actions, including the potential cellular mechanisms responsible as a result of stimulating or inhibiting the two arms of this novel CYP pathway. The therapeutic potential of increasing EET concentrations and/or reducing 20-HETE concentrations will also be addressed.
Gross
Garrett J
GJ
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ggross@mcw.edu
Falck
John R
JR
Gross
Eric R
ER
Isbell
Marilyn
M
Moore
Jeannine
J
Nithipatikom
Kasem
K
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D015398:Signal Transduction
D006893:Hydroxyeicosatetraenoic Acids; D015221:Potassium Channels; D011453:Prostaglandins; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid