CYP-eicosanoids—A new link between omega-3 fatty acids and cardiac disease?

Fish oil omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against arrhythmia and sudden cardiac death by largely unknown mechanisms. Recent in vitro and in vivo studies demonstrate that arachidonic acid (AA) metabolizing cytochrome P450-(CYP) enzymes accept EPA and DHA as efficient alternative substrates. Dietary EPA/DHA supplementation causes a profound shift of the cardiac CYP-eicosanoid profile from AA- to EPA- and DHA-derived epoxy- and hydroxy-metabolites. CYP2J2 and other CYP epoxygenases preferentially epoxidize the ω-3 double bond of EPA and DHA. The corresponding metabolites, 17,18-epoxy-EPA and 19,20-epoxy-DHA, dominate the CYP-eicosanoid profile of the rat heart after EPA/DHA supplementation. The (ω-3)-epoxyeicosanoids show highly potent antiarrhythmic properties in neonatal cardiomyocytes, suggesting that these metabolites may specifically contribute to the cardioprotective effects of omega-3 fatty acids. This hypothesis is discussed in the context of recent findings that revealed CYP-eicosanoid mediated mechanisms in cardiac ischemia–reperfusion injury and maladaptive cardiac hypertrophy.

► EPA and DHA protect against arrhythmia and sudden cardiac death.
► CYP enzymes efficiently hydroxylate and epoxidize EPA and DHA.
► Dietary EPA/DHA supplementation modulates the cardiac CYP eicosanoid profile.
► CYP-dependent (ω-3)-epoxyeicosanoids exhibit potent antiarrhythmic properties.
► (ω-3)-Epoxyeicosanoids may mediate cardioprotective signaling pathways.