Details

Autor(en) / Beteiligte

• Darwesh, Ahmed M.
• Seubert, John M.

Titel

CYP‐Derived Epoxy Metabolites of Docosahexaenoic Acid Protect the Heart against Ischemia/Reperfusion Injury via Inhibition of NLRP3 Inflammasome Pathway

Ist Teil von

• The FASEB journal, 2019-04, Vol.33 (S1), p.513.8-513.8

Ort / Verlag

The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• Objective Recent evidence suggests that impaired mitochondrial function and activation of the NOD‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasome cascade have a role in the adverse outcomes following myocardial ischemia‐reperfusion (IR) injury. Dietary long‐chain omega‐3 polyunsaturated fatty acids (n−3 PUFAs) are essential constituents of the body, which have protective effects against cardiovascular diseases. There is growing evidence indicating 19,20‐epoxydocosapentaenoic acid (19,20‐EDP), generated by CYP450 epoxygenase‐mediated metabolism of the n3‐PUFA docosahexaenoic Acid (DHA), mediate many of the beneficial effects. However, 19,20‐EDP is hydrolyzed and inactivated by the soluble epoxide hydrolase (sEH). Therefore, the current study hypothesized that direct administration or inhibiting the degradation of 19,20‐EDP ameliorates IR injury by maintaining mitochondrial quality and inhibiting the activation of the NLRP3 cascade. Methods Hearts isolated from wild type (WT) or sEH null mice were perfused in the Langendorff mode for 40 min of baseline and subjected to 30 min of global no flow ischemia followed by 40 min of reperfusion. Hearts were treated with either vehicle, DHA (10 μM), 19,20‐EDP (1 μM) or the specific sEH inhibitor trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB, 0.1 μM). Postischemic functional recovery of left ventricular developed pressure (LVDP) was used to determine protective responses. Cytosolic and mitochondrial heart fractions were assessed for changes in mitochondrial dynamics and NLRP3 inflammasome complex. Mitochondrial respiration was assessed in permeabilized cardiac fibers at the end of reperfusion. Results Improved postischemic functional recovery and mitochondrial function were observed in hearts perfused with 19,20‐EDP or hearts where sEH was deleted or pharmacologically inhibited. The activation of the NLRP3 inflammasome complex was significantly induced by IR injury in WT and vehicle control hearts. Perfusion with 19,20‐EDP or inhibition of sEH markedly attenuated activation of NLRP3 inflammasomes. Perfusion with DHA or 19,20‐EDP limited the degradation of the mitochondrial fusion protein Optic atrophy‐1 (Opa‐1) and prevented the mitochondrial localization of the fission protein Dynamin‐related protein‐1 (Drp‐1) induced by IR injury. DHA and 19,20‐EDP were able to maintain the antioxidants activities of cytosolic thioredoxin (Trx)‐1 and mitochondrial Trx‐2 under IR conditions. DHA‐mediated cardioprotective effects were attenuated by the specific CYP epoxygenase inhibitor N‐(methylsulfonyl)‐2‐(2‐propynyloxy)‐benzenehexanamide (MSPPOH, 50 μM). Conclusion Together, these data suggest that the CYP‐derived metabolite of DHA, 19,20‐EDP, protects against IR injury by maintaining mitochondrial function and reducing a detrimental innate inflammatory response. Support or Funding Information Support for this project was provided by the Canadian Institutes of Health Research. This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.