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Open AccessArticle

A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3–NLRP3 Pathway

1
Faculty of Pharmacy and Pharmaceutical Sciences, 2026-M Katz Group Centre for Pharmacy and Health Research, University of Alberta, 11361-97 Ave, Edmonton, AB T6G 2E1, Canada
2
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
3
Division of Chemistry, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
*
Author to whom correspondence should be addressed.
In memoriam.
Int. J. Mol. Sci. 2020, 21(15), 5261; https://doi.org/10.3390/ijms21155261
Received: 26 May 2020 / Revised: 20 July 2020 / Accepted: 21 July 2020 / Published: 24 July 2020
(This article belongs to the Special Issue Inflammasome)
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. View Full-Text
Keywords: ischemia-reperfusion injury; EDP surrogates; cardioprotection; mitochondria; Sirtuin 3; NLRP3 inflammasome ischemia-reperfusion injury; EDP surrogates; cardioprotection; mitochondria; Sirtuin 3; NLRP3 inflammasome
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MDPI and ACS Style

Darwesh, A.M.; Bassiouni, W.; Adebesin, A.M.; Mohammad, A.S.; Falck, J.R.; Seubert, J.M. A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3–NLRP3 Pathway. Int. J. Mol. Sci. 2020, 21, 5261. https://doi.org/10.3390/ijms21155261

AMA Style

Darwesh AM, Bassiouni W, Adebesin AM, Mohammad AS, Falck JR, Seubert JM. A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3–NLRP3 Pathway. International Journal of Molecular Sciences. 2020; 21(15):5261. https://doi.org/10.3390/ijms21155261

Chicago/Turabian Style

Darwesh, Ahmed M.; Bassiouni, Wesam; Adebesin, Adeniyi M.; Mohammad, Abdul S.; Falck, John R.; Seubert, John M. 2020. "A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3–NLRP3 Pathway" Int. J. Mol. Sci. 21, no. 15: 5261. https://doi.org/10.3390/ijms21155261

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