A synthetic epoxydocosapentaenoic acid analogue ameliorates cardiac ischemia/reperfusion injury: The involvement of the sirtuin 3–nlrp3 pathway

Ahmed M. Darwesh, Wesam Bassiouni, Adeniyi Michael Adebesin, Abdul Sattar Mohammad, John R. Falck, John M. Seubert

Research output: Contribution to journalArticle

Abstract

While survival rates have markedly improved following cardiac ischemia-reperfusion (IR) injury, the resulting heart damage remains an important issue. Preserving mitochondrial quality and limiting NLRP3 inflammasome activation is an approach to limit IR injury, in which the mitochondrial deacetylase sirtuin 3 (SIRT3) has a role. Recent data demonstrate cytochrome P450 (CYP450)-derived epoxy metabolites, epoxydocosapentaenoic acids (EDPs), of docosahexaenoic acid (DHA), attenuate cardiac IR injury. EDPs undergo rapid removal and inactivation by enzymatic and non-enzymatic processes. The current study hypothesizes that the cardioprotective effects of the synthetic EDP surrogates AS-27, SA-26 and AA-4 against IR injury involve activation of SIRT3. Isolated hearts from wild type (WT) mice were perfused in the Langendorff mode with vehicle, AS-27, SA-26 or AA-4. Improved postischemic functional recovery, maintained cardiac ATP levels, reduced oxidative stress and attenuation of NLRP3 activation were observed in hearts perfused with the analogue SA-26. Assessment of cardiac mitochondria demonstrated SA-26 preserved SIRT3 activity and reduced acetylation of manganese superoxide dismutase (MnSOD) suggesting enhanced antioxidant capacity. Together, these data demonstrate that the cardioprotective effects of the EDP analogue SA-26 against IR injury involve preservation of mitochondrial SIRT3 activity, which attenuates a detrimental innate NLRP3 inflammasome response.

Original languageEnglish (US)
Article number5261
Pages (from-to)1-21
Number of pages21
JournalInternational journal of molecular sciences
Volume21
Issue number15
DOIs
StatePublished - Aug 2020

Keywords

  • Cardioprotection
  • EDP surrogates
  • Ischemia-reperfusion injury
  • Mitochondria
  • NLRP3 inflammasome
  • Sirtuin 3

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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