Cardiac ischemia/reperfusion injury is associated with the formation and action of lipid mediators derived from polyunsaturated fatty acids. Among them, linoleic acid (LA) is metabolized to epoxyoctadecanoic acids (EpOMEs) by cytochrome P450 (CYP) epoxygenases and further to dihydroxyoctadecanoic acids (DiHOMEs) by soluble epoxide hydrolase (sEH). We hypothesized that EpOMEs and/or DiHOMEs may affect cardiac post-ischemic recovery and addressed this question using isolated murine hearts in a Langendorff system. Hearts from C57Bl6 mice were exposed to 12,13-EpOME, 12,13-DiHOME, or vehicle (phosphate buffered sodium; PBS). Effects on basal cardiac function and functional recovery during reperfusion following 20 min of ischemia were investigated. Electrocardiogram (ECG), left ventricular (LV) pressure and coronary flow (CF) were continuously measured. Ischemia reperfusion experiments were repeated after administration of the sEH-inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). At a concentration of 100 nM, both EpOME and DiHOME decreased post-ischemic functional recovery in murine hearts. There was no effect on basal cardiac parameters. The detrimental effects seen with EpOME, but not DiHOME, were averted by sEH inhibition (AUDA). Our results indicate that LA-derived mediators EpOME/DiHOME may play an important role in cardiac ischemic events. Inhibition of sEH could provide a novel treatment option to prevent detrimental DiHOME effects in acute cardiac ischemia.
Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease.
Title: Palmitic Acid Methyl Ester and Its Relation to Control of Tone of Human Visceral Arteries and Rat Aortas by Perivascular Adipose Tissue Wang N, Kuczmanski A, Dubrovska G, Gollasch M Ref: Front Physiol, 9:583, 2018 : PubMed
Background: Perivascular adipose tissue (PVAT) exerts anti-contractile effects on visceral arteries by release of various perivascular relaxing factors (PVRFs) and opening voltage-gated K(+) (Kv) channels in vascular smooth muscle cells (VSMCs). Palmitic acid methyl ester (PAME) has been proposed as transferable PVRF in rat aorta. Here, we studied PVAT regulation of arterial tone of human mesenteric arteries and clarified the contribution of Kv channels and PAME in the effects. Methods: Wire myography was used to measure vasocontractions of mesenteric artery rings from patients undergoing abdominal surgery. Isolated aortic rings from Sprague-Dawley rats were studied for comparison. PVAT was either left intact or removed from the arterial rings. Vasocontractions were induced by external high K(+) (60 mM), serotonin (5-HT) or phenylephrine. PAME (10 nM-3 muM) was used as vasodilator. Kv channels were blocked by XE991, a Kv7 (KCNQ) channel inhibitor, or by 4-aminopyridine, a non-specific Kv channel inhibitor. PAME was measured in bathing solutions incubated with rat peri-aortic or human visceral adipose tissue. Results: We found that PVAT displayed anti-contractile effects in both human mesenteric arteries and rat aortas. The anti-contractile effects were inhibited by XE991 (30 muM). PAME (EC50 ~1.4 muM) was capable to produce relaxations of PVAT-removed rat aortas. These effects were abolished by XE991 (30 muM), but not 4-aminopyridine (2 mM) or NDGA (10 muM), a lipoxygenases inhibitor. The cytochrome P450 epoxygenase inhibitor 17-octadecynoic acid (ODYA 10 muM) and the soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA 10 muM) slightly decreased PAME relaxations. PAME up to 10 muM failed to induce relaxations of PVAT-removed human mesenteric arteries. 5-HT induced endogenous PAME release from rat peri-aortic adipose tissue, but not from human visceral adipose tissue. Conclusions: Our data also suggest that Kv7 channels are involved in the anti-contractile effects of PVAT on arterial tone in both rat aorta and human mesenteric arteries. PAME could contribute to PVAT relaxations by activating Kv7 channels in rat aorta, but not in human mesenteric arteries.
BACKGROUND: Single nucleotide polymorphisms (SNPs) of EPHX2 alter sEH activity and are associated with increased [rs41507953 (K55R)] or reduced [rs751141 (R287Q)] cardiovascular risk via modulation of fibrosis, inflammation or cardiac ion channels. This indicates an effect on development and therapy response of AF. This study tested the hypothesis that variations in the EPHX2 gene encoding human soluble epoxide hydrolase (sEH) are associated with atrial fibrillation (AF) and recurrence of atrial fibrillation after catheter ablation. METHODS AND RESULTS: A total of 218 consecutive patients who underwent catheter ablation for drug refractory AF and 268 controls were included. Two SNPs, rs41507953 and rs751141, were genotyped by direct sequencing. In the ablation group, holter recordings 3, 12 and 24months after ablation were used to detect AF recurrence. No significant association of the SNPs and AF at baseline was detected. In the ablation group, recurrence of AF occurred in 20% of the patients 12months after ablation and in 35% 24months after ablation. The presence of the rs751141 polymorphism significantly increased the risk of AF recurrence 12months (odds ratio [OR]: 3.2, 95% confidence interval [CI]: 1.237 to 8.276, p=0.016) and 24months (OR: 6.076, 95% CI: 2.244 to 16.451, p<0.0001) after catheter ablation. CONCLUSIONS: The presence of rs751141 polymorphism is associated with a significantly increased risk of AF recurrence after catheter ablation. These results point to stratification of catheter ablation by genotype and differential use of sEH-inhibitory drugs in the future.
