Inhibition of Soluble Epoxide Hydrolase Limits Mitochondrial Damage and Preserves Function Following Ischemic Injury

Abstract

Aims: Myocardial ischemia can result in marked mitochondrial damage leading to cardiac dysfunction, as such identifying novel mechanisms to limit mitochondrial injury is important. This study investigated the hypothesis that inhibiting soluble epoxide hydrolase (sEH), responsible for converting epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids protects mitochondrial from injury caused by myocardial infarction.Methods: sEH null and WT littermate mice were subjected to surgical occlusion of the left anterior descending (LAD) artery or sham operation. A parallel group of WT mice received an sEH inhibitor, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; 10 mg/L) or vehicle in the drinking water 4 days prior and 7 days post-MI. Cardiac function was assessed by echocardiography prior- and 7-days post-surgery. Heart tissues were dissected into infarct, peri-, and non-infarct regions to assess ultrastructure by electron microscopy. Complexes I, II, IV, citrate synthase, PI3K activities, and mitochondrial respiration were assessed in non-infarct regions. Isolated working hearts were used to measure the rates of glucose and palmitate oxidation.Results: Echocardiography revealed that tAUCB treatment or sEH deficiency significantly improved systolic and diastolic function post-MI compared to controls. Reduced infarct expansion and less adverse cardiac remodeling were observed in tAUCB-treated and sEH null groups. EM data demonstrated mitochondrial ultrastructure damage occurred in infarct and peri-infarct regions but not in non-infarct regions. Inhibition of sEH resulted in significant improvements in mitochondrial respiration, ATP content, mitochondrial enzymatic activities and restored insulin sensitivity and PI3K activity.Conclusion: Inhibition or genetic deletion of sEH protects against long-term ischemia by preserving cardiac function and maintaining mitochondrial efficiency.

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats

“…This EET-B treatment prior to ischemia in SHR could have additional effects on acute cardiac ischemic tolerance as suggested by the reduction of life-threating arrhythmias [ 19 ]. In addition, the improved post-MI LV function is more likely attributable to EET-B beneficial actions during CHF progression as it was previously demonstrated for other EET-based pharmacological interventions [ 8 , 10 , 11 , 18 , 37 , 48 ]. Finally, in a recent work we demonstrated that sEH inhibitor c-AUCB and EET analog EET-A, given alone or in combination at reperfusion attenuated the progression of post-MI LV systolic dysfunction only in Sprague-Dawley but not in hypertensive Ren-2 transgenic rats in spite of blood pressure reduction [ 19 , 49 ].…”

“…It has been shown that NUDSA, an earlier generation EET analog, improved cardiac function in mice after MI [ 18 ]. Moreover, an attenuation of post-MI LV dysfunction progression has been reported in rats and mice treated with various sEH inhibitors [ 8 , 10 , 11 , 37 , 48 ]. In line with these earlier findings, we demonstrated that EET-B treatment (started two weeks before MI and continued till seven weeks after MI) attenuated post-MI LV systolic dysfunction and adverse changes of ventricular geometry in the present study.…”

Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity

“…Ischemia-reperfusion injury can lead to accumulation of protective EETs after the release of fatty acids by membrane-bound phospholipases (Seubert et al, 2004). Increasing EETs in an sEH null mouse model showed limited mitochondrial damage after ischemia compared with wild-type (Akhnokh et al, 2016). EETs can enforce their cardioprotective effects through the activation of mitoK (ATP) and opening of the mitochondrial membrane permeability pore (Barau et al, 2015).…”

“…Furthermore, the treatment period used by Alsaad and colleagues may not be sufficient to induce many of the characteristic features of chronic DOX cardiotoxicity. A detailed assessment by Cove-Smith et al (2014) of both cardiac Cyclosporine A (Tang et al, 2011) Hypertension, tachycardia, myocardial infarction Oxidative stress and/or mitochondrial dysfunction In a CYP2J2 transgenic mouse, heart failure-induced oxidative stress was mitigated by EETs; EETs increased expression of antioxidant enzymes and reduced ROS levels (Wang et al, 2014;Akhnokh et al, 2016).…”

“…In sEH null mice, increased circulating EETs limited mitochondrial damage following ischemia (Akhnokh et al, 2016) Amiodarone (Isomoto et al, 2006) Ventricular fibrillation, ventricular tachycardia, QTc prolongation.…”