Cardioprotective Action of a Novel Synthetic 19,20-EDP Analog Is Sirt Dependent.

Autor:	Kranrod JW; Faculty of Pharmacy and Pharmaceutical Sciences, 2026-M Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada.; Cardiovascular Research Institute, University of Alberta, Edmonton, AB, Canada., Darwesh AM; Faculty of Pharmacy and Pharmaceutical Sciences, 2026-M Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada., Bassiouni W; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Huang A; Faculty of Pharmacy and Pharmaceutical Sciences, 2026-M Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada., Fang L; Cardiovascular Research Institute, University of Alberta, Edmonton, AB, Canada.; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Korodimas JV; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Adebesin AM; Division of Chemistry, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX; and., Munnuri S; Division of Chemistry, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX; and.; TCG GreenChem, Inc, Process R&D Center at Princeton South, Ewing, NJ., Falck JR; Division of Chemistry, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX; and., Seubert JM; Faculty of Pharmacy and Pharmaceutical Sciences, 2026-M Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada.; Cardiovascular Research Institute, University of Alberta, Edmonton, AB, Canada.; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Jazyk:	angličtina
Zdroj:	Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 2024 Jan 01; Vol. 83 (1), pp. 105-115. Date of Electronic Publication: 2024 Jan 01.
DOI:	10.1097/FJC.0000000000001495
Abstrakt:	Abstract: Mounting evidence suggests that cytochrome P450 epoxygenase-derived metabolites of docosahexaenoic acid, called epoxydocosapentaenoic acids (EDPs), limit mitochondrial damage after cardiac injury. In particular, the 19,20-EDP regioisomer has demonstrated potent cardioprotective action. Thus, we investigated our novel synthetic 19,20-EDP analog SA-22 for protection against cardiac ischemia-reperfusion (IR) injury. Isolated C57BL/6J mouse hearts were perfused through Langendorff apparatus for 20 minutes to obtain baseline function, followed by 30 minutes of global ischemia. Hearts were then treated with vehicle, 19,20-EDP, SA-22, or SA-22 with the pan-sirtuin inhibitor nicotinamide or the SIRT3-selective inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) at the start of 40 minutes reperfusion (N = 5-8). We assessed IR injury-induced changes in recovery of myocardial function, using left ventricular developed pressure and systolic and diastolic pressure change. Tissues were assessed for electron transport chain function, SIRT1 and SIRT3, optic atrophy type 1, and caspase-1. We also used H9c2 cells in an in vitro model of hypoxia/reoxygenation injury (N = 3-6). Hearts perfused with SA-22 had significantly improved postischemic left ventricular developed pressure, systolic and diastolic recovery (64% of baseline), compared with vehicle control (15% of baseline). In addition, treatment with SA-22 led to better catalytic function observed in electron transport chain and SIRT enzymes. The protective action of SA-22 resulted in reduced activation of pyroptosis in both hearts and cells after injury. Interestingly, although nicotinamide cotreatment worsened functional outcomes, cell survival, and attenuated sirtuin activity, it failed to completely attenuate SA-22-induced protection against pyroptosis, possibly indicating EDPs exert cytoprotection through pleiotropic mechanisms. In short, these data demonstrate the potential of our novel synthetic 19,20-EDP analog, SA-22, against IR/hypoxia-reoxygenation injury and justify further development of therapeutic agents based on 19,20-EDP. Competing Interests: The authors report no conflicts of interest. (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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