2006 George E. Brown Memorial Lecture—The CYP450 Pathway and Cardioprotection
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 proinflammatory 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 other organs. In this presentation, I will discuss the detrimental and beneficial actions of this novel pathway, including the potential cellular mechanisms responsible for the effects observed as a result of stimulating or inhibiting the 2 arms of this novel CYP450 pathway. The therapeutic potential of increasing EET concentrations and/or reducing 20-HETE concentrations will also be addressed.