Cardioprotective effects of CYP-derived epoxy metabolites of docosahexaenoic acid involve limiting NLRP3 inflammasome activation 1

Can J Physiol Pharmacol. 2019 Jun;97(6):544-556. doi: 10.1139/cjpp-2018-0480. Epub 2018 Oct 16.


Impaired mitochondrial function and activation of NLRP3 inflammasome 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 acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (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 of ischemia and followed by 40 min of reperfusion. In contrast with 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 as 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 N-(methysulfonyl)-2-(2-propynyloxy)-benzenehexanamide. 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.

Keywords: 19,20-epoxydocosapentaenoic acid; NLRP3 inflammasome; acide 19,20-époxydocosapentaénoïque; acide docosahexaénoïque; blessure d’ischémie–reperfusion; cœur; docosahexaenoic acid; heart; inflammasomes NLRP3; ischemia–reperfusion injury; mitochondria; mitochondrie.

MeSH terms

  • Animals
  • Cardiotonic Agents / metabolism
  • Cardiotonic Agents / pharmacology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Docosahexaenoic Acids / metabolism*
  • Docosahexaenoic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Epoxy Compounds / metabolism*
  • Female
  • Inflammasomes / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*


  • Cardiotonic Agents
  • Epoxy Compounds
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Docosahexaenoic Acids
  • Cytochrome P-450 Enzyme System