Influence of inflammation on cardiovascular protective effects of cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids.

In addition to their role as xenobiotic metabolizing enzymes, cytochrome P450 (CYP) epoxygenases actively contribute to the metabolism of endogenous substances such as arachidonic acid. Epoxyeicosatrienoic acids (EETs) are epoxide derivative of arachidonic acid. CYP2C8/9 and CYP2J2 are the main epoxygenases expressed in human tissues including endothelial cells which are the chief sources of EET formation in human body. Once formed, EETs are primarily metabolized to their less biologically active metabolites, dihydroxyeicosatrienoic acids, by soluble epoxy hydrolase (sEH) enzyme. EETs possess a wide range of established protective effects on human cardiovascular system of which vasodilatory, angiogenic and anti-inflammatory actions have been more extensively described. On the other hand, inflammation has shown to decrease the expression and activity of CYP enzyme, including epoxygenases. Given the fact that CYP epoxygenase-derive EETs exhibit potent cardiovascular protective effects, including anti-inflammation, and that inflammation suppress CYP activation and EET formation, it would make sense to speculate that under inflammatory conditions there exists an inflammation-epoxygenase-EET-inflammation vicious cycle in which the inflammation-induced downregulation of CYP epoxygenases causes a decrease in the EET production. Insufficient EET synthesis would, in turn, lead to an ineffective EET-mediated anti-inflammatory effect, leading to an augmentation of systemic and regional inflammatory responses and further downregulation of CYP epoxygenase activity/EET production. This cycle, if any, might help to better understanding of pathophysiology of chronic cardiovascular diseases and also could be an emerging target for further pharmacological therapy of disorders in which increased inflammatory responses are known to occur.