Deficiency of Soluble Epoxide Hydrolase Protects Cardiac Function Impaired by LPS-Induced Acute Inflammation

Abstract

Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Linoleic acid (18:2n6, LA) is an essential n-6 PUFA which is converted to arachidonic acid (20:4n6, AA) by desaturation and elongation via enzyme systems within the body. Biological transformation of PUFA through CYP-mediated hydroxylation, epoxidation, and allylic oxidation produces lipid mediators, which may be subsequently hydrolyzed to corresponding diol metabolites by soluble epoxide hydrolase (sEH). In the current study, we investigate whether inhibition of sEH, which alters the PUFA metabolite profile, can influence LPS induced cardiotoxicity and mitochondrial function. Our data demonstrate that deletion of soluble epoxide hydrolase provides protective effects against LPS-induced cardiotoxicity by maintaining mitochondrial function. There was a marked alteration in the cardiac metabolite profile with notable increases in sEH-derived vicinal diols, 9,10- and 12,13-dihydroxyoctadecenoic acid (DiHOME) in WT hearts following LPS administration, which was absent in sEH null mice. We found that DiHOMEs triggered pronounced mitochondrial structural abnormalities, which also contributed to the development of extensive mitochondrial dysfunction in cardiac cells. Accumulation of DiHOMEs may represent an intermediate mechanism through which LPS-induced acute inflammation triggers deleterious alterations in the myocardium in vivo and cardiac cells in vitro. This study reveals novel research exploring the contribution of DiHOMEs in the progression of adverse inflammatory responses toward cardiac function in vitro and in vivo.

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

“…CYP-dependent oxidation of LA results in the production of epoxyoctadecanoic acids (EpOME), which are rapidly metabolized by sEH to their corresponding diol metabolites, dihydroxyoctadecanoic acids (DiHOME) [ 187 ]. Evidence from animal and in vitro studies has suggested DiHOMEs are potent cytotoxic metabolites [ 212 ]. Increased levels of cardiac DiHOMEs are thought to be associated with deteriorated myocardial electrical activity, altered ion channel kinetics, depressed LV function and impaired mitochondrial respiration [ 213 , 214 , 215 , 216 ].…”

“…There is limited information regarding the adverse impact of DiHOMEs toward cardiac function and aging. However, evidence suggests the myocardial accumulation of 12, 13-DiHOME correlates with LPS-induced cytotoxicity and a decline in mitochondrial function and cell survival [ 212 ]. The 12,13-DiHOME-augmented release of ROS and mitochondrial dysfunction in hearts exposed to ischemia-reperfusion is associated with diminished myocardial functional recovery [ 213 ].…”

“…Therefore, targeting mitochondrial dysfunction in the aging myocardium is an unmet need holding significant promise for age-related cardiac diseases. Although the exact mechanisms of how epoxylipids regulate cardiac function are not fully understood, accumulating data suggest mitochondria-targeted effects are an important component of their cardioprotective properties [ 203 , 212 , 238 ]. Numerous in vivo and ex vivo studies demonstrate sEH inhibition or treatment with epoxylipids improve LV functional recovery in murine hearts following ischemia-reperfusion injury protecting mitochondrial function and ultrastructure [ 181 , 206 , 225 , 238 , 239 , 240 , 241 ].…”

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

“…The level of MDA was assessed in the cardiac tissue using a lipid peroxidation (MDA) colorimetric assay kit (ab118970, Abcam, Burlingame, CA, USA) according to manufacturer's instructions [41,52]. In this assay, free MDA present in the sample reacts with thiobarbituric acid (TBA) and generate a MDA-TBA adduct which was quantified colorimetrically at wavelength 532 nm.…”

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

“…Several studies were carried out to investigate the effect of the sEH gene deletion [17][18][19]. Samokhvalov et al reported that such a deletion provides a protective effect against lipopolysaccharide (LPS)-induced cardiotoxicity by maintaining mitochondrial function [20]. In their research associated with Parkinson's disease, Ren et al reported that sEH gene deletion or enzyme inhibition may protect against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced neurotoxicity [21].…”