Cardioprotective Effects of CYP-Derived Epoxy Metabolites of Docosahexaenoic Acid Involve Limiting NLRP3 Inflammasome Activation.

Impaired mitochondrial function and activation of NLRP3 inflammasomes cascade has a significant role in the pathogenesis of myocardial ischemia-reperfusion (IR) injury. The current study investigated whether eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or their corresponding CYP epoxygenase metabolites, 17,18-epoxyeicosatetraenoic acids (17,18-EEQ) and 19,20-epoxydocosapentaenoic acids (19,20-EDP), protect against IR injury. Isolated mouse hearts were perfused in the Langendorff mode with vehicle, DHA, 19,20-EDP, EPA or 17,18-EEQ and subjected to 30 min schemia and followed by 40 min of reperfusion. In contrast to EPA and 17,18-EEQ, DHA and 19,20-EDP exerted cardioprotection, as shown by a significant improvement in postischemic functional recovery associated with significant attenuation of NLRP3 inflammasome complex activation and preserved mitochondrial function. Hearts perfused with DHA or 19,20-EDP displayed a marked reduction in localization of mitochondrial Drp-1 and Mfn-2 as well maintained Opa-1 levels. DHA and 19,20-EDP preserved the activities of both the cytosolic Trx-1 and mitochondrial Trx-2. DHA cardioprotective effect was attenuated by the CYP epoxygenase inhibitor MSPPOH. In conclusion, our data indicate a differential cardioprotective response between DHA, EPA and their active metabolites toward IR injury. Interestingly, 19,20-EDP provided the best protection against IR injury via maintaining mitochondrial function and thereby reducing the detrimental NLRP3 inflammasome responses.