Cardioprotective mechanisms of cytochrome P450 derived oxylipins from ω-3 and ω-6 PUFAs

The seminal discovery that cytochrome P450 enzymes (CYPs) can oxidize polyunsaturated fatty acids (PUFAs) sparked a new area of research aimed at discovering the role of these metabolites in cardiac physiology and pathophysiology. CYPs metabolize arachidonic acid, an ω-6 PUFA, to alcohols and epoxides with the latter providing cardioprotection following myocardial infarction, hypertrophy, and diabetes-induced cardiomyopathy through their anti-inflammatory, vasodilatory and antioxidant properties. Despite their protective properties, the use of EETs as therapeutic agents is hampered mainly by their rapid hydrolysis to less active vicinal diols by soluble epoxide hydrolase (sEH). Several approaches have been investigated to prolong EET signaling effects using small molecule sEH inhibitors, chemically and biologically stable analogs of EETs and more recently, through the development of an sEH vaccine. Alternatively, research investigating the cardioprotective outcomes of ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly focused on dietary intake or supplementation studies. EPA and DHA have overlapping but distinct effects on myocardial function and merit separate studies to fully understand their mechanism of cardiac protection. In contrast to EETs, relatively fewer studies examined the protective mechanisms of EPA and DHA derived epoxides to determine if some protective effects are in part due to the CYP mediated downstream metabolites. The actions of CYPs on PUFAs generate potent oxylipins utilizing diverse cardioprotective mechanisms and the extent of their full potential will be important for the future development of therapeutics to prevent or treat cardiovascular disease.