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.
Highlights
Exposure to the bacterial endotoxin lipopolysaccharide (LPS), a major component of the cell wall from Gram-negative bacteria, can trigger acute systemic reactions potentially leading to multiple organ failure (Lew et al, 2013)
In order to assess whether soluble epoxide hydrolase (sEH) deficiency provides resistance, we induced acute inflammation in WT and sEH null mice using a clinically relevant model where LPS was administrated i.p. (10 mg/kg)
There were no significant differences between WT and sEH null mice in either control or LPS groups for eNOS and TLR4 proteins
Summary
Exposure to the bacterial endotoxin lipopolysaccharide (LPS), a major component of the cell wall from Gram-negative bacteria, can trigger acute systemic reactions potentially leading to multiple organ failure (Lew et al, 2013). Prevailing theories attribute these failures to uncontrolled inflammatory responses that produce numerous deleterious effects such as extensive organelle dysfunction and cell death (Lew, 2003; Kozlov et al, 2011; Lew et al, 2013). The precise mechanisms by which adverse acute inflammatory reactions lead to organ failure are not clear, evidence suggests mitochondrial dysfunction is an important cause in the progression of cardiac failure (Frantz et al, 1999; Callahan and Supinski, 2005; Anderson et al, 2007)
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