Triglyceride-rich lipoprotein (TGRL) lipolysis products provide a pro-inflammatory stimulus that can alter endothelial barrier function. To probe the mechanism of this lipolysis-induced event, we evaluated the pro-inflammatory potential of lipid classes derived from human postprandial TGRL by lipoprotein lipase (LpL). Incubation of TGRL with LpL for 30 min increased the saturated and unsaturated FFA content of the incubation solutions significantly. Furthermore, concentrations of the hydroxylated linoleates 9-hydroxy ocatadecadienoic acid (9-HODE) and 13-HODE were elevated by LpL lipolysis, more than other measured oxylipids. The FFA fractions elicited pro-inflammatory responses inducing TNFa and intracellular adhesion molecule expression and reactive oxygen species (ROS) production in human aortic endothelial cells (HAECs). The FFA-mediated increase in ROS was blocked by both the cytochrome P450 2C9 inhibitor sulfaphenazole and NADPH oxidase inhibitors. Compared with linoleate, 13-HODE was found to be a more potent inducer of ROS production in HAECs, an activity that was insensitive to both NADPH oxidase and cytochrome P450 inhibitors. Therefore, although the oxidative metabolism of FFA in endothelial cells can produce inflammatory responses, TGRL lipolysis can also release preformed mediators of oxidative stress (e.g., HODEs) that may influence endothelial cell function in vivo by stimulating intracellular ROS production.-Wang, L., R. Gill, T. L. Pedersen, L. J. Higgins, J. W. Newman, and J. C. Rutledge. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J. Lipid Res. 2009. 50: 204-213.

Arachidonic acid-derived epoxides, epoxyeicosatrienoic acids, are important regulators of vascular homeostasis and inflammation, and therefore manipulation of their levels is a potentially useful pharmacological strategy. Soluble epoxide hydrolase converts epoxyeicosatrienoic acids to their corresponding diols, dihydroxyeicosatrienoic acids, modifying or eliminating the function of these oxylipins. To better understand the phenotypic impact of Ephx2 disruption, two independently derived colonies of soluble epoxide hydrolase-null mice were compared. We examined this genotype evaluating protein expression, biofluid oxylipin profile, tissue oxylipin production capacity, and blood pressure. Ephx2 gene disruption eliminated soluble epoxide hydrolase protein expression and activity in liver, kidney, and heart from each colony. Plasma levels of epoxy fatty acids were increased, and fatty acid diols levels were decreased, while measured levels of lipoxygenase-and cyclooxygenase-dependent oxylipins were unchanged. Liver and kidney homogenates also show elevated epoxide fatty acids. However, in whole kidney homogenate a 4-fold increase in the formation of 20-hydroxyeicosatetraenoic acid was measured along with a 3-fold increase in lipoxygenase-derived hydroxylation and prostanoid production. Unlike previous reports, however, neither Ephx2-null colony showed alterations in basal blood pressure. Finally, the soluble epoxide hydrolase-null mice show a survival advantage following acute systemic inflammation. The data suggest that blood pressure homeostasis may be achieved by increasing production of the vasoconstrictor, 20-hydroxyeicosatetraenoic acid in the kidney of the Ephx2-null mice. This shift in renal metabolism is likely a metabolic compensation for the loss of the soluble epoxide hydrolase gene. Soluble epoxide hydrolase (sEH)3 is a ubiquitous enzyme found in many tissues such as liver, kidney, heart, and ovary (1). sEH catalyzes the degradation of endogenous epoxy lipids such as epoxyeicosatrienoic acids (EETs) to their less active diols (dihydroxyeicosatrienoic acids, DHETs) and hence plays a critical role in the control of EET levels (2). These epoxy lipids are potent vasodilators, regulating cerebral and renal homodynamic and blood pressure (3-5). In addition, EETs inhibit platelet aggregation (6), promote fibrinolysis (7) and have antiinflammatory properties (8, 9). Whereas deletion of the sEH gene, Ephx2, has been reported to reduce blood pressure in male mice (10), the inhibition of endogenous EET hydrolysis may provide pharmacological benefit in hypertension and acute inflammation (11).The human Ephx2 gene encodes sEH and consists of 19 exons encoding 555 amino acids (12). There is 73% homology between the human and mouse sEH protein sequences (13), with 100% conservation in the catalytic residues (14). Each monomer of the homodimeric mouse sEH has two distinct domains (14,15). The N-terminal domain exhibits phosphatase activity, and the C-terminal domain is responsible for the epoxide hydrolase activities (...

Abstract-Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na ϩ diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto-prostaglandin F1␣ was unaffected by salt loading but was dramatically increased 7-to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The saltstimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load. T he dietary intake of linoleic acid (LA), an essential fatty acid, influences blood pressure. Increased dietary LA intake reduces systolic blood pressure, increases red blood cell membrane LA content, and alters red and white blood cell sodium transport processes in clinical studies. 1-7 Conversely, dietary LA deprivation in rats results in the development of salt-sensitive hypertension and an inability to excrete an acute salt load, with both effects reversed by the administration of LA. 8 -10 LA is a precursor of arachidonic acid, and it has been proposed that the effects of LA on blood pressure and salt excretion may be mediated through the production of various cytochrome P450 (CYP) eicosanoids and/or prostaglandins, including the epoxyeicosatrienoic acids (EETs) [11][12][13][14] and the prostacyclin metabolite 6-keto-prostaglandin (PG) F1␣. 15,16 Inhibition of CYP-mediated EET production has been associated with the development of hypertension in rats. 11 Dietary salt loading upregulates CYP2C23 in rats, increasing EET production and inhibiting Na ϩ reabsorption, whereas low-salt diets suppress this enzyme. 12,14 The EETs have also been shown to directly inhibit the distal tubule epithelial sodium channel. 13,14 LA, however, also serves as a substrate in various oxygenation r...

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