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

Abstract

Mounting evidence suggests that CYP epoxygenase-derived metabolites of docosahexaenoic acid, called epoxydocosapentaenoic acids (EDPs), limit mitochondrial damage following 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 IR injury. Isolated C57BL/6J mouse hearts were perfused via Langendorff apparatus for 20 minutes to obtain baseline function followed by 30 minutes of global ischemia. Hearts were then treated with either vehicle, 19,20-EDP, SA-22, or SA-22 with the pan-sirtuin inhibitor nicotinamide (NAM), 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, systolic and diastolic pressure change. Tissues were assessed for ETC function, SIRT-1 and -3, optic atrophy type-1, and caspase-1. We also utilized H9c2 cells in an in vitro model of hypoxia/reoxygenation injury (N=3-6). Hearts perfused with SA-22 had significantly improved postischemic LVDP, systolic and diastolic recovery (64% of baseline), compared to 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 or cells following injury. Interestingly, while NAM co-treatment 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/HR injury and justifies further development of therapeutic agents based upon 19,20-EDP.

Cardioprotective properties of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids

“…Our current results also demonstrate that OMT-28 improved the post-ischemic functional recovery of isolated perfused mouse hearts subjected to IR injury in a Langendorff apparatus. This cardioprotective effect involved limiting NLRP3 inflammasome activation associated with caspase-1 activation and subsequent IL-1β expression, similarly, as reported before with 19,20-EDP ( 12 , 13 ). NLRP3 inflammasome activation has been generally known to play a central role in myocardial IR injury ( 103 ).…”

“…Together, the current data supports a concept where OMT-28 enhances and sustains optimal mitochondrial quality following HR injury. Taking 19,20-EDP as an example, we speculate that OMT-28 activates not only SIRT1 but also SIRT3 which deacetylates MnSOD and thereby directly reduces O 2 − -production in mitochondria ( 13 , 102 ). Rapid post-translational activation of MnSOD would also be in line with our finding that OMT-28 acutely inhibits O 2 − -production if added only in the reoxygenation phase.…”

“…These n-3-derived FA epoxides (n-3 EpFA) display pleiotropic effects including cardioprotective ( 5 , 6 ), antihypertensive ( 7 ), anti-inflammatory ( 8 , 9 , 10 ), and antifibrotic ( 11 ) properties that may contribute to the beneficial effects of n-3 LC-PUFAs in cardiovascular disease ( 2 ). Preclinical animal studies demonstrate synthetic analogs of n-3 epoxyeicosanoids can ameliorate ischemia-reperfusion injury ( 12 , 13 ), laser-induced choroidal neovascularization ( 8 ), and LPS-induced endotoxemia ( 14 ).…”