Impact of circulating esterified eicosanoids and other oxylipins on endothelial function

Abstract

Eicosanoids, including epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and other oxylipins derived from polyunsaturated fatty acids, have emerging roles in endothelial inflammation and subsequent atherosclerosis. Unlike eicosanoids in the prostanoid series, they are known to be esterified in cell lipids such as phospholipids and triglycerides; however, our understanding of these reservoirs is in its infancy. This review focuses on recent work identifying circulating oxylipins, primarily esterified with lipoprotein lipids, and their effects on markers of endothelial dysfunction. These oxylipins are known to be released by at least one lipase (lipoprotein lipase) and to mediate increased expression of inflammatory markers in endothelial cells, which coincides with the known roles of lipoproteins in endothelial dysfunction. The implications of the lipolytic release of lipoprotein-bound oxylipins for the inflammatory response, challenges to analysis of this oxylipin compartment, and the potential importance of non-arachidonate-derived oxylipins are discussed.

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

“…Furthermore, >90% of plasma EETs are esterifi ed to lipoprotein phospholipids in rats and humans (35)(36)(37). The direct functional role of cellular and circulating esterifi ed EETs, however, remains unclear and requires further investigation ( 34,35 ). It is important to note that free plasma oxylipins were quantifi ed in the current investigation, and that changes in circulating lipoprotein levels have been reported to impact the relative extent of oxylipin esterifi cation into lipoprotein phospholipids ( 36,37 ).…”

“…Although the aforementioned cellular and physiological effects have been attributed to free EETs, and sEH rapidly hydrolyzes free EETs to their corresponding DHET metabolites, it is well-established that cellular EETs are readily esterifi ed to membrane phospholipids ( 6,34 ). Furthermore, >90% of plasma EETs are esterifi ed to lipoprotein phospholipids in rats and humans (35)(36)(37). The direct functional role of cellular and circulating esterifi ed EETs, however, remains unclear and requires further investigation ( 34,35 ).…”

“…*QEA P < 0.05 and FDR q < 0.05. of free EET concentrations, as opposed to both free and total concentrations, is a limitation of the current study because we cannot conclusively determine whether increased EET esterifi cation to lipoprotein phospholipids contributed, at least in part, to the observed results. Indeed, an improved understanding of the biological and therapeutic relevance of EET incorporation into phospholipids is of considerable interest to the fi eld ( 35 ). Future studies that quantify free and total EET levels are needed to further elucidate the mechanisms underlying the relationship between advanced CAD and lower EET levels in humans.…”

Arachidonic Acid-metabolizing Cytochrome P450 Enzymes Are Targets of ω-3 Fatty Acids*

“…Error bars, S.E. diated release (62,63). Also, in this compartment, dietary EPA/ DHA supplementation resulted in a significant replacement of EETs and 20-HETE by EEQs/EDPs and 20-HEPE/22-HDoHE.…”

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

“…Our previous study in rats demonstrated that the shift from AA-derived CYP-epoxygenase metabolites to EPA-and DHA-derived CYP-epoxygenase metabolites occurred with largely identical effi ciencies in the plasma, heart, kidney, liver, lung, and pancreas ( 22 ). Moreover, the circulating epoxy-metabolites that are predominantly esterifi ed with lipoprotein lipids may themselves become biologically active in other tissues after being released by lipoprotein lipases ( 81 ). There is increasing evidence for a cardioprotective role of CYP-epoxygenase metabolites from studies in animal models of ischemia/reperfusion injury, maladaptive cardiac hypertrophy, and arrhythmia ( 12,24,82 ).…”