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ReviewAdvances in Cardiovascular Geroscience

Dietary modulation of oxylipins in cardiovascular disease and aging

Published Online:01 Nov 2017https://doi.org/10.1152/ajpheart.00201.2017

Abstract

Oxylipins are a group of fatty acid metabolites generated via oxygenation of polyunsaturated fatty acids and are involved in processes such as inflammation, immunity, pain, vascular tone, and coagulation. As a result, oxylipins have been implicated in many conditions characterized by these processes, including cardiovascular disease and aging. The best characterized oxylipins in relation to cardiovascular disease are derived from the ω-6 fatty acid arachidonic acid. These oxylipins generally increase inflammation, hypertension, and platelet aggregation, although not universally. Similarly, oxylipins derived from the ω-6 fatty acid linoleic acid generally have more adverse than beneficial cardiovascular effects. Alternatively, most oxylipins derived from 20- and 22-carbon ω-3 fatty acids have anti-inflammatory, antiaggregatory, and vasodilatory effects that help explain the cardioprotective effects of these fatty acids. Much less is known regarding the oxylipins derived from the 18-carbon ω-3 fatty acid α-linolenic acid, but clinical trials with flaxseed supplementation have indicated that these oxylipins can have positive effects on blood pressure. Normal aging also is associated with changes in oxylipin levels in the brain, vasculature, and other tissues, indicating that oxylipin changes with aging may be involved in age-related changes in these tissues. A small number of trials in humans and animals with interventions that contain either 18-carbon or 20- and 22-carbon ω-3 fatty acids have indicated that dietary-induced changes in oxylipins may be beneficial in slowing the changes associated with normal aging. In summary, oxylipins are an important group of molecules amenable to dietary manipulation to target cardiovascular disease and age-related degeneration.

NEW & NOTEWORTHY Oxylipins are an important group of fatty acid metabolites amenable to dietary manipulation. Because of the role they play in cardiovascular disease and in age-related degeneration, oxylipins are gaining recognition as viable targets for specific dietary interventions focused on manipulating oxylipin composition to control these biological processes.

all tissues in the body contain oxylipins, which are bioactive lipids that are endogenously produced via the oxygenation of polyunsaturated fatty acids. Their involvement in cardiovascular disease and aging includes their roles in innate immunity, inflammation, cardiac function, blood coagulation, and vascular tone regulation. Because they are derived from polyunsaturated fatty acids, dietary interventions involving these (e.g., ω-6 and ω-3 fatty acids) may prove to be an effective strategy in altering concentrations of deleterious or beneficial oxylipins. The recent advances in mass spectrometry techniques have increased the awareness of the vast number of oxylipins that are present and those that are altered by dietary manipulations. In addition, the enzymes responsible for their production, as well as the receptors to which they bind, are also potential targets for manipulating oxylipin levels. This review will highlight the physiological and pathophysiological role of oxylipins in cardiovascular disease and aging as well as how concentrations of oxylipins can be altered nutritionally.

Enzymes in the Production of Oxylipins

Upon cell activation, oxylipin formation begins when fatty acids are released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2). Although phospholipids are thought to be the primary source of fatty acid for oxylipin formation, lack of cPLA2 does not completely abolish oxylipin formation (2, 153). Oxylipins may be formed by other means, such as through triacylglycerol lipase, as evidenced in mast cells (44). Once released, these fatty acids are converted to oxylipins via three main pathways: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CYP) epoxygenase and ω-hydroxylase. COX enzymes have dioxygenase activity, thus donating two oxygen molecules to the fatty acid substrate to form a 5-carbon ring structure at the 8- to 12-carbon positions of 20-carbon fatty acids. This process forms PGH, which is then further metabolized to several prostanoids [PGs and thromboxanes (TXs)] via enzymes specific for these prostanoids. The most well known of COX-derived oxylipins are the eicosanoids derived from arachidonic acid (AA), but prostanoids also are formed from dihomo-γ-linolenic acid (e.g., PGE1), eicosapentaenoic acid (EPA) (e.g., PGE3), and adrenic acid (e.g., dihomo-PGE2) (58, 98). These prostanoids are produced via two different isomers of COX, namely, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues, whereas COX-2 can be induced by inflammation to produce oxylipins that can propagate the inflammatory response. Inhibitors of COX such as acetaminophen, ibuprofen, and acetylsalicylic acid reduce the concentration of COX products and thus reduce fever, pain, and coagulation (57, 98, 165).

Many other enzymes that further metabolize COX oxylipins are also targets for pharmaceutical development. For example, TX synthase is responsible for converting PGH2 to TXA2, which is a potent vasoconstrictor. Ozagrel is a pharmaceutical TX synthase inhibitor that improves neurological function after an acute ischemic stroke in humans (220). However, the use of Ozagrel is not supported by the Food and Drug Administration, as its clinical safety and efficacy are still being investigated (196). Another enzyme of interest in oxylipin metabolism is PGI2 synthase. PGI2 synthase converts PGH2 to PGI2, which is a vasodilator. An experimental agonist of PGI2 and a TX synthase inhibitor (ONO-1301) was tested in an animal model of hypertension and resulted in a decrease in blood pressure (130).

LOX is similar to COX, as it donates two oxygen molecules to its substrate in the formation of hydroperoxy derivatives of fatty acids. LOX enzymes are typically classified based on their formation of the resulting hydroxy derivatives of AA (e.g., 5-LOX, 12-LOX, and 15-LOX). However, the hydroxylation site varies with different fatty acids and often displays some promiscuity. The same homolog can have different positional specificities in different species, so the hydroxylation site naming system is limited; an alternate nomenclature has been proposed based on the gene names (18, 104). Further metabolism of LOX oxylipins (sometimes including epoxygenase and LOX activities) results in the formation of many other oxylipins, including leukotrienes (LTs), eoxins, hepoxilins, lipoxins (LXs), maresins (MaRs), protectins (PDs), and resolvins (Rvs) (17, 142, 160, 162). Pharmaceuticals have been developed to target LOX enzymes, such as Zileuton, to reduce the concentration of hydroxy-eicosatetraenoic acids (HETEs) and LT. This LOX inhibitor was developed to reduce inflammatory conditions, such as asthma (177).

The third oxylipin pathway includes the epoxygenase and ω-hydroxylase activities of a large number of CYP enzymes. Epoxygenase activity results in the formation of epoxygenated fatty acids such as epoxy-eicosatrienoic acid (EpETrE; often abbreviated as EET) derived from AA (134). These epoxy fatty acids are further metabolized by soluble epoxide hydrolase (sEH) to the dihydroxy form [e.g., dihydroxy-eicosatetraenoic acid (DiHETrE); often abbreviated as DHET]. Analogs of oxylipins from linoleic acid (LA), α-linolenic acid (ALA), γ-linolenic acid, dihomo-γ-linolenic acid, adrenic acid, EPA, and docosahexaenoic acid (DHA) also are formed by CYP epoxygenase activity (58, 100, 164, 182). ω-Hydroxylase activity results in hydroxylation of the carbons close to the methyl (ω) end of the fatty acid. For example, oxylipins formed from AA via this activity result in 16- to 20-HETE. Inhibitors of sEH have been developed for antihypertensive and cardioprotective effects. sEH is ubiquitously expressed and in particularly high concentrations in the liver, kidney, and blood vessels (48, 181). The latest pharmaceutical inhibitors of sEH are derived from urea and amides that are active site transition state mimetics. Inhibition of sEH increases concentrations of the more vasodilatory EpETrEs by preventing their metabolism to the DiHETrEs that have less vasodilatory activity (81, 91).

Oxylipins are generally formed in situ by these three major enzymatic pathways and act as autocrine and paracrine mediators. They also can be formed transcellularly, thus allowing cells that do not have the complete set of enzymes available to produce oxylipins (29). Their effects are mediated by binding to G protein-coupled receptors or to intracellular effectors, such as peroxisome proliferator-activated receptor-γ, among others that are still being elucidated (14, 18, 57, 100, 164, 182). Many oxylipins interact with multiple receptors that are characterized by their most potent biological ligand. Receptor isoforms also exist and often have differing effects. For example, PGE2 can bind to the EP3 receptor, which has prothrombotic effects, or to EP4, which has antithrombotic effects (84). Further details on oxylipin receptors, enzymes, and further metabolism of oxylipins to more metabolites can be found in available reviews (14, 17, 18, 57, 58, 100, 104, 142, 160, 162, 164, 165, 182). Nonenzymatically derived oxylipins also can be formed, with many being used as markers of oxidative stress (e.g., isoprostanes). Further discussion of these in relation to health and disease can be found elsewhere (128).

Roles of Oxylipins in Cardiovascular Disease

Oxylipins, and more specifically the eicosanoids produced from AA, have long been implicated in atherosclerosis, platelet aggregation, vascular constriction, and cardiac injury and dysfunction. For select examples of oxylipins with cardiovascular functions, see Table 1. Eicosanoids therefore have been and continue to be targets for the treatment and prevention of heart disease. A well-researched inhibitor of eicosanoids is the COX inhibitor acetylsalicylic acid (i.e., aspirin), as the association of COX products with cardiovascular disease has been well documented. For example, patients with stable angina pectoris compared with normal subjects exhibit significantly higher concentrations of circulating TXB2, and those with variant angina exhibit markedly elevated levels of TXB2 during an episode of angina (187). In addition, patients with genetic variations for TX and PGI2 synthases are at a higher risk for developing a myocardial infarction or ischemic stroke (109). Aspirin has been implicated in lowering cardiovascular disease risk because it alters several COX oxylipins involved. For example, it decreases the concentration of the proaggregatory and vasoconstrictive TXA2 while having less effect on the antiaggregatory and vasodilatory PGI2 (183a, 193, 199). Other COX oxylipins also have cardiovascular effects, such as PGE2, which is involved in cardiac hypertrophy and ischemia (78, 120), and PGF2α, which is produced and associated with dysfunction in the stressed heart and also plays a role in cardiac hypertrophy (1, 72). In comparison, PGD2 can inhibit platelet aggregation and polymorphonuclear neutrophil degranulation (19, 39, 212) and may be protective against ischemia-reperfusion injury (92).

Table 1. Select oxylipins and physiological/pathophysiological effects associated with cardiovascular disease

OxylipinPhysiological/Pathophysiological Effect
Linoleic acid
9-HODE
13-HODE		HODEs are produced via the LOX pathway. They are present in human monocyte-oxidized LDL and associated with oxidative stress (54, 79).
9-HODE induces macrophage IL-1β (102).
9-HODE and 13-HODE activate plasminogen activator inhibitor type-1 via PPAR-γ activation in endothelial cells (116).
13-HODE prevents platelets from adhering to human vascular endothelial cells (16, 191).
9,10-DiHOME
12,13-DiHOME		DiHOMEs are produced by the metabolism of EpOMEs (also known as leukotoxins) by sEH and are associated with oxidative stress and inflammation in endothelial cells (124, 204).
Plasma concentrations of the DiHOMEs are decreased after flaxseed ingestion in patients with peripheral artery disease and hypertension (21).
Dihomo-γ-linolenic acid
15-HETrE15-HETrE is produced via 15-LOX and can inhibit 5-LOX in human polymorphonuclear leukocytes (145).
Arachidonic acid
PGD2PGD2 is produced via the COX pathway and can inhibit platelet aggregation (19, 211).
PGD2 either has no effect on vascular tone or can constrict and dilate mesenteric arteries in dogs (61).
PGD2 has been implicated in the innate immune response (172).
PGD2 inhibits human platelet aggregations and polymorphonuclear neutrophil degranulation (39).
15-deoxy-PGJ215-Deoxy-PGJ2 is a PGD2 metabolite that activates plasminogen activator inhibitor type-1 via PPAR-γ activation in endothelial cells (116).
PGE2PGE2 is produced via the COX pathway and can induce renal vascular resistance in rats (8).
PGE2 can either be proinflammatory and vasoconstrictive or anti-inflammatory and vasodilatory depending on which EP receptor it binds (34).
PGE2 is involved in cardiac hypertrophy and ischemia (77, 119).
6-keto-PGF1α6-Keto-PGF1α is the stable metabolite and marker of PGI2 that is produced via the COX pathway.
6-Keto-PGF1α in human plasma is inversely related to cardiovascular events and high central blood pressure (22, 27).
PGI2 is an endothelium-derived oxylipin with vasodilatory and antiaggregatory activity (33, 45).
PGI2 reduces pulmonary vascular resistance in humans (118).
PGF2αPGF2α is produced via the COX pathway and induces vasoconstriction in bovine, canine, and human coronary arteries (104).
PGF2α is associated with dysfunction in the stressed heart and with cardiac hypertrophy (1, 71).
TXB2TXB2 is the stable metabolite and marker of the short-lived TXA2 that is produced via the COX pathway.
TXA2 is an endothelium-derived oxylipin that potently induces vasoconstriction and aggregation of platelets (33).
TXB2 is positively associated with high central blood pressure and multiple cardiovascular events (22, 27).
LTsLTs are produced via the 5-LOX pathway and are associated with atherosclerosis, endothelial dysfunction, intimal hyperplasia, and cytokine release (7).
LTB4 is chemotactic and stimulates neutrophil lysosomal degranulation of human neutrophils (66).
5-HETE
8-HETE
9-HETE
11-HETE
12-HETE
15-HETE		HETEs are produced via LOX pathways.
5-HETE is chemotactic for human neutrophils (62, 64) and inhibits PGI2 production in porcine coronary artery endothelial cells (68).
5-, 8-, 9-, 11-, and 12-HETE stimulate migration, chemotaxis, and chemokinesis in multiple leukocytes (63, 65, 96, 184), whereas 15-HETE appears to have opposite effects (179, 189).
12- and 15-HETE have both pro- and antiaggregatory effects, depending on the model system and aggregant (35, 55, 86, 169, 170, 173).
15-HETE also can be converted to the LXs, which play a role in the resolution of inflammation (17).
5,12-DiHETE5,12-HETE is produced via by sequential 5- and 12-LOX activity and is chemotactic for human neutrophils (64).
5,6-EpETrE
8,9-EpETrE
11,12-EpETrE
14,15-EpETrE		EpETrEs are formed via the CYP epoxygenase pathway and are endothelial-derived hyperpolarizing factors.
EpETrEs vasodilate isolated canine coronary arterioles and preconstricted pressurized mouse arteries (76, 138).
EpETREs induce hyperpolarization and relaxation of the vasculature (97).
11,12-EpETrE improve recovery of cardiac contractility in a rat model of ischemia/reperfusion (214).
14,15-EpETrE reduces postischemic electrocardiogram abnormalities (9).
5,6-DiHETrE
8,9-DiHETrE
11,12-DiHETrE
14,15-DiHETrE		DiHETrEs are produced by sEH from EpETrEs. The conversion of the EpETrE to the DiHETrEs causes a concomitant loss of vasodilation (76, 100) in some, but not all, cases (76).
DiHETrEs in plasma decrease following flaxseed ingestion in patients with peripheral artery disease and hypertension (21).
DiHETrEs vasodilate isolated canine coronary arterioles and preconstricted pressurized mouse arteries (76, 138).
Plasma 5,6-DiHETrE is associated with high central blood pressure (27), and 11,12-DiHETrE is associated with multiple cardiovascular events (22) in patients with peripheral artery disease.
16-HETE
18-HETE
19-HETE
20-HETE		16-HETE through 20-HETE are produced by CYP ω-hydroxylase activity. 16-HETE is produced by polymorphonuclear leukocytes and is released upon ANG II stimulation (10).
When administered intravenously, 16-HETE lowers intracranial pressure after a thromboembolic stroke in New Zealand White rabbits (11).
16-HETE, 18-HETE, and 19-HETE and metabolites of 20-HETE can promote vasodilation (30, 50, 88, 113).
20-HETE is a vasoconstrictor in small porcine coronary arteries (150).
Eicosapentaenoic acid
PGD3PGD3 inhibits human platelet aggregation with similar or greater activity than PGD2 (211).
PGI3PGI3 inhibits aggregation in human and rabbit platelets (99, 132).
LTB5LTB5 is produced via the 5-LOX pathway and is much less chemotactic but stimulates neutrophil lysosomal degranulation with similar potency as LTB4 in human neutrophils (66).
LTB5 is less inflammatory than LTB4 in polymorphonuclear leukocytes, lungs, and transplanted tissue (107, 121, 122).
5-HEPE
12-HEPE		5-HEPE and 12-HEPE are produced via the LOX pathway.
5-HEPE promotes bovine neutrophil chemotaxis in vitro but is less potent than 5-HETE (75).
12-HEPE inhibits human platelet aggregation similarly to 12-HETE (188).
5-oxo-EPE5-Oxo-EPE is produced from 5-HEPE and is 10% as potent in stimulating neutrophils as 5-oxo-eicosatetraenoic acid formed from arachidonic acid (146).
8,9-EpETE
11,12-EpETE
14,15-EpETE
17,18-EpETE		EpETEs are produced via the CYP epoxygenase pathway. They inhibit platelet aggregation, display vasodilatory effects, and exhibit antiarrhythmic effects in neonatal cardiomyocytes (6, 98, 105, 216).
18-HEPE18-HEPE is produced via the CYP ω-hydroxylase pathway and is a precursor to E-series resolvins, which can reduce neutrophil migration and inflammatory responses (136).
Docosahexaenoic acid
14-HDoHE
17-HDoHE		14-HDoHE and 17-HDoHE are produced by the LOX pathway and are precursors to maresin, protectin, and D-series resolvins, respectively, which are inflammation-resolving mediators.
14-HDoHE can antagonize platelet activation (35).
17-HDoHE vasodilates bovine coronary arterial smooth muscle cells (110).
HDoHEs can also be produced via autooxidation in vitro and therefore have been implicated as potential markers of oxidative stress (201).
HDoHE plasma levels decreased with flaxseed ingestion (23, 27).
7,8-EpDPE
10,11-EpDPE
13,14-EpDPE
16,17-EpDPE
19,10-EpDPE		EpDPEs are produced via the CYP epoxygenase pathway and inhibit platelet aggregation and TXA2 synthesis (98).
EpDPEs dilate porcine coronary arterioles (216).
19,20-EpDPE decreases human platelet aggregation (87).
MaR
PD
RvD		Maresin, protectin, and D-series resolvins are produced from 14-HDoHE and 17-HDoHE.
These mediators are antiaggregatory (32, 212), resolve inflammation, and prevent neutrophil transmigration (136, 171, 172).
Resolvin D can increase the production of nitric oxide and PGI2 in endothelial cells (182). Protectin DX exhibits antiaggregatory effects (32, 150)

HODE, hydroxy-octadecadienoic acid; LOX, lipoxygenase; PPAR, peroxisome proliferator-activated receptor; DiHOME, dihydroxy-octadecenoic acid; EpOME, epoxy-octadecenoic acid; sEH, soluble epoxide hydrolase; HETrE, hydroxy-eicosatrienoic acid; COX, cyclooxygenase; TX, thromboxane; LT, leukotriene; HETE, hydroxy-eicosatetraenoic acid; CYP, cytochrome P-450; HEPE, hydroxy-eicosapentaenoic acid; 5-oxo-EPE, 5-oxo-eicosapentaenoic acid; EpETE, epoxy-eicosatetraenoic acid; HDoHE, hydroxy-docosahexaenoic acid; EpDPE, epoxy-docosapentaenoic acid.

In two landmark trials, aspirin significantly reduced the incidence of myocardial infarction and cardiovascular events (47). The Physician’s Health Study and the British Doctor’s Trial both observed an average 32% reduction in the incidence of a first myocardial infarction and a 15% reduction in vascular events with aspirin (47). In a trial including nearly 40,000 women, low-dose aspirin (100 mg), provided every second day for 10 yr, did not lower the risk of cardiovascular events in women aged >45 yr but did reduce the risk of cardiovascular events in women aged >65 yr (154). It is important to note that selective COX-2 inhibitors such as rofecoxib have resulted in a greater risk of developing cardiovascular events compared with naproxen. This is thought to be due to a reduction in the production of the protective antiaggregatory PGI2 by rofecoxib (125). It appears that this increased risk of cardiovascular events with this drug is not found with other COX-2 inhibitors, however. Nevertheless, prolonged NSAID use is associated with gastrointestinal, renal, and cardiovascular side effects that need to be considered with their use, as reviewed in many recent publications (71, 144, 203). This provides evidence for the importance of the COX oxylipins in cardiovascular disease.

Another group of oxylipins that have been investigated for their impact on cardiovascular disease via proinflammatory effects are LTs derived via the LOX pathway. There is a clear association of inflammatory disease and cardiovascular disease; atherosclerosis is characterized frequently as a chronic inflammatory condition (42). The mechanisms whereby inflammatory reactions and infectious disease are involved in atherosclerotic cardiovascular disease can include endothelial interactions, foam cell formation, smooth muscle cell proliferation, promotion of atherothrombosis, and via cytokine and chemokine production (42). LTs have been implicated in the progression of atherosclerosis because of their role in inflammation as well as in endothelial dysfunction, intimal hyperplasia, and cytokine release (7). LTB4 is chemotactic and stimulates neutrophil lysosomal degranulation of human neutrophils (65), and inhibition of LTs by competitive exclusion from their respective receptors reduces infarct size, intimal hyperplasia, and atherosclerosis in experimental models (157).

Like the LTs, several HETEs are also produced by the LOX pathway and have been implicated in platelet aggregation, vasoconstriction, and inflammation. For example, 12- and 15-HETE have both pro- and antiaggregatory effects, depending on the model system and aggregant (35, 55, 87, 170, 171, 174), and 5-HETE inhibits PGI2 production in porcine coronary artery endothelial cells (69). Many HETE isomers (5-, 8-, 9-, 11-, and 12-HETE) stimulate migration, chemotaxis, and chemokinesis in multiple leukocytes (62, 64, 185, 198), whereas 15-HETE may have the opposite effects (180, 190). 15-HETE also can be converted to LXs, which play a role in the resolution of inflammation (17).

Other HETEs are produced via the CYP ω-hydroxylase pathway, including 16- to 20-HETE produced from AA. The production of 20-HETE is stimulated by angiotensin II and endothelin-1 in vascular smooth muscle cells, and inhibition of the formation of 20-HETE reduces the impact of angiotensin II and endothelin-1 on the vasculature (134). 20-HETE induces vasoconstriction in canine renal arteries and porcine coronary arteries (151). On the other hand, 16-, 18-, and 19-HETE and metabolites of 20-HETE can promote vasodilation (30, 50, 89, 114). Therefore, the balance of the various isomers of HETE is of key importance in vascular tone regulation and thus cardiovascular disease.

The role of CYP-derived EpETrEs is a rapidly developing area of research because of their impact on vasodilation. They are endothelium-derived hyperpolarizing factors that increase the open state probability of Ca2+-activated K+ channels in coronary smooth muscle cells (28). EpETrEs accomplish this by activating the transient receptor potential (TRP)V4 channel to import Ca2+, which activates the ryanodine receptor to induce a Ca2+ spark. Ca2+ sparks activate the Ca2+-activated K+ channel to induce hyperpolarization and relaxation of the vasculature (98). EpETrEs are quickly metabolized by sEH to DiHETrEs, in which a concomitant loss of vasodilation occurs. Maintaining EpETrE concentrations by reducing the production of DiHETrE through pharmacological sEH inhibition (83) induces a reduction in blood pressure in models of hypertension (82, 83, 132), reduces vascular smooth muscle cell proliferation (101), and inhibits inflammatory pain processes (135). Interestingly, however, DiHETrE can have similar or even greater vasodilatory activity than EpETrE under some conditions (77, 139), and polymorphisms in the EpETrE-producing CYP enzymes do not always correlate with effects on hypertension; more remains to be understood in this regard, as reviewed elsewhere (12).

EpETrEs also have protective effects directly on the heart, such as improving recovery from ischemia and electrocardiogram abnormalities in isolated rodent hearts (9, 163, 215) and suppressing the endoplasmic reticulum stress response in heart failure (208). They also have many other cardioprotective effects on heart injury related to ischemia-reperfusion injury, drug-induced cardiotoxicity, pressure overload, and cardiac hypertrophy, as previously reviewed (85, 161, 210).

Thus, although AA-derived oxylipins generally have proaggregatory, vasoconstrictive, and inflammatory effects that would have detrimental effects on cardiovascular health, not all (e.g., CYP products above) function in this way, and a comprehensive evaluation of the oxylipin profile is needed to assess the overall effects. In a recent investigation of nearly 100 patients with cardiovascular disease (22), the prevalence of transient ischemic attacks, strokes, angina, and acute coronary syndrome was studied to determine whether plasma oxylipins or fatty acids were related to cardiovascular/cerebrovascular events. None of the 24 fatty acids quantified were associated with any of these cardiovascular events. However, 8 of the nearly 40 plasma oxylipins identified known to regulate vascular tone were significantly associated with these clinical events. For example, plasma 16-HETE was more than four times higher in patients that suffered from a cerebrovascular accident versus those that did not. Plasma 8,9-DiHETrE increased the odds by 92-fold of acute coronary syndrome. Only the stable PGI2 metabolite 6-keto-PGF1α was associated with a protective effect with an odds ratio of <1 for the prevalence of transient ischemic attacks. For every one-unit increase in the TXB2 to 6-keto-PGF1α ratio and every 1 nM increase in plasma 16-HETE, TXB2, or 11,12-DiHETrE, the odds of having had at least two events versus no event increased. Although the conclusions from this study are limited by the relatively small sample size in both patient population and the overall number of clinical events, the results clearly warrant further, more extensive study of the relationship of oxylipins with clinical events.

Nutritional Interventions Altering Oxylipins in Cardiovascular Diseases

The oxylipin profile in tissues is determined not only by the relative abundance of the oxylipin-synthesizing and -metabolizing enzymes but also by the polyunsaturated fatty acids present, which is influenced greatly by the composition of dietary fatty acids. The correlation between dietary polyunsaturated fatty acid intake and tissue concentrations of these same fatty acids is relatively high; one report indicated a ρ value of 0.96 between dietary ALA:LA to renal concentrations of ALA:LA (24).

Although oxylipins derived from AA are the best characterized and primarily the ones described above, oxylipins derived from other polyunsaturated fatty acids also must be considered in dietary recommendations. For example, LOX and CYP oxylipins derived from LA have been associated with atherosclerosis and inflammation (103, 141, 219) but also have been related to anti-inflammatory, antiproliferative, and antiplatelet effects (16, 79, 176, 192, 223). The LA oxylipin 13-hydroxy-octadecadienoic acid (13-HODE) is enriched in oxidized LDL and may contribute to the accumulation of macrophages in atherosclerotic plaques (175), suggesting a detrimental role for this oxylipin in atherosclerosis progression. This may be relevant to the ongoing debate regarding recommendations to increase dietary LA to reduce the risk of cardiovascular disease by reducing blood lipids (20). Indeed, increasing the levels of LA in the diet not only increases the levels of LA oxylipins (which can make up more than half of all oxylipins by mass) but also may increase the levels of AA-derived oxylipins, as has been illustrated in rat tissues (110, 150, 188).

Dietary interventions with ω-3 fatty acids are more commonly recommended for reduction in cardiovascular disease risk. With respect to oxylipins, those derived from ω-3 fatty acids tend to have less activity or opposite effects than ω-6-derived oxylipins, although this is not always the case. Because they can compete with the same enzymes and receptors as their ω-6 counterparts, further diminution of the biological effects of ω-6 oxylipins can occur (74, 102, 133). For example, TXA3 derived from EPA is produced less efficiently than TXA2 derived from AA, as EPA is generally a poorer substrate for COX and inhibits production of AA oxylipins (133, 206). On the other hand, PGI3 has similar vasodilatory and antiaggregatory activity as PGI2, resulting in a less aggregatory and vasoconstrictive state when EPA is present in the diet (133). With respect to LOX metabolites, LTB5 derived from EPA is less inflammatory than LTB4 (108, 122, 123), 5-oxo-eicosapentaenoic acid (5-oxo-EPE) derived from EPA is 10% as potent in stimulating neutrophils as its AA oxylipin counterpart (191), and 14-hydroxy-docosahexaenoic acid (14-HDoHE) can antagonize platelet activation (35). CYP-derived epoxy-eicosatetraenoic acids (EpETEs; often abbreviated as EEQ) formed from EPA and epoxy-docosapentaenoic acids (EpDPEs, often abbreviated as EDP) formed from DHA also inhibit platelet aggregation and TXA2 synthesis with greater potency than their counterparts formed from AA (200), and EpETEs display similar or greater vasodilatory activity than EpETrEs in some vascular beds (106, 217). EpETEs also exhibit antiarrhythmic effects in neonatal cardiomyocytes by inhibiting Ca2+ and isoproterenol-induced contractility in these cells (6). The recently discovered MaRs and Rvs derived from DHA and EPA also are involved in the resolution of inflammation by preventing neutrophil transmigration in murine models of inflammation (137, 172, 173). Rv also can increase the production of nitric oxide and PGI2 as well as decrease the production of adhesion molecules and reactive oxygen species in endothelial cells (183). A similar molecule, protectin DX (PDX), exhibits antiaggregatory effects (32, 151).

Oxylipins in the blood can be rapidly altered with dietary fat, as shown with the presence of increased levels of oxylipins in the circulation in as little as 2–6 h after consumption of a ω-3 fatty acid-enriched milkshake or supplementation (169, 184) or in longer-term studies with fish oil supplements (52, 93, 166, 168). Therefore, there is great potential through dietary intervention to alter the endogenous oxylipin profile and through this mechanism reduce the risk of proinflammatory conditions, such as hypertension and cardiovascular disease. Much evidence exists for the protective effects of ω-3 fatty acids derived from fish oils on risk for cardiovascular disease, as discussed in a recent science advisory from the American Heart Association (178), which concluded that ω-3 fatty acids were beneficial in patients with prevalent coronary heart disease. However, many studies also have failed to find a protective effect of ω-3 fatty acid supplementation in cardiovascular disease, as discussed in several recent reviews (15, 152, 155). These findings are confounded by a number of limitations in many studies, such as small sample size, short treatment periods, use of low dosages, and effects of high use of cardiovascular drugs for those at highest risk. Several of these limitations are presently being tested in several large randomized clinical trials that should provide more clarity to this issue (NCT00135226, NCT01169259, NCT01492361, and NCT02104817). The protective effects of oxylipins derived from 20- and 22-carbon ω-3 fatty acids as outlined above are considered an important component of the mechanism by which these fatty acids would mediate their protective effects and have been reviewed in further detail elsewhere (49, 70, 86, 211).

In addition, oxylipins derived from the 18-carbon ω-3 fatty acid ALA may also reduce the risk of cardiovascular disease. Although several studies have provided evidence of the protective effect of dietary ALA in cardiovascular disease (reviewed in Refs. 53, 70, and 95), little is known regarding its effects on oxylipins. In the FLAX effects in Peripheral Arterial Disease (FlaxPAD) trial (156), patients who received 30 g of ground flaxseed daily for 6 mo demonstrated a significant reduction in brachial systolic (−10 mmHg) and diastolic (−7 mmHg) blood pressure. A strong inverse relationship of blood pressure with plasma levels of ALA (the main fatty acid in flaxseed) was observed in this study (156). Interestingly, subsequent analyses revealed that ALA exhibited a significant inhibitory effect on the activity of sEH (21). sEH is a rate-limiting enzyme in the generation of several key dihydroxy-octadecenoic acids (DiHOMEs; also known as leukotoxin diols) and DiHETrEs. These oxylipins increase inflammation and cytotoxicity and generally have less vasodilatory activity than their epoxy precursors. Dietary flaxseed reduced the levels of all six of the DiHOMEs and DiHETrEs examined. Thus, as shown in Fig. 1, the reduction in blood pressure by dietary flaxseed may have been induced by an elevation in circulating ALA, which would inhibit sEH activity and thereby 1) reduce the levels of inflammatory DiHOME (inflammation is thought to induce hypertension) and 2) decrease the loss of vasodilation by decreasing the conversion of DiHETrE from EpETrE (21). These actions are consistent with ongoing studies testing the antihypertensive efficacy of drugs that inhibit sEH (40, 83, 132).

Fig. 1.

Fig. 1.Proposed mechanism whereby dietary flaxseed reduces blood pressure through the modulation of circulating oxylipin levels. ALA, α-linolenic acid; sEH, soluble epoxide hydrolase; EpOME, epoxy-octadecenoic acid (also known as leukotoxin); DiHOME, dihydroxy-octadecenoic acid (also known as leukotoxin diols); EpETrE, epoxy-eicosatrienoic acid (also abbreviated as EET); DiHETrE, dihydroxy-eicosatrienoic acid (also abbreviated as DHET). [Modified from Caligiuri et al. (21).]

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Another potential antihypertensive action of ALA is the ability to reduce the concentration of other proinflammatory oxylipins. Consumption of ground flaxseed by older healthy adults for 4 wk reduced the circulating levels of 5-HETE and two LA-derived oxylipins, 9,10,13- and 9,12,13-trihydroxy-octadecenoic acid (TriHOMEs), which are characterized by their proinflammatory properties (175). Indeed, 5-HETE is reported to be the most chemotactic of the HETE family and promotes neutrophil recruitment (62). This may in part explain the capacity of an ALA-enriched diet maintained for 6 wk to reduce peripheral blood mononuclear cell production of interleukin-6, interleukin-1, and tumor necrosis factor-α in hypercholesterolemic patients (105).

In addition to effects on peripheral blood pressure, the effects of dietary flaxseed on central blood pressure were also examined in the FlaxPAD study (27). In patients with diagnosed hypertension, average decreases in central systolic and diastolic blood pressure versus the control were 10 and 6 mmHg, respectively. The circulating concentrations of several oxylipins such as TXB2, 6-keto-PGF1α, and 5,6-DiHETrE were associated with central systolic blood pressure, central diastolic blood pressure, and central mean blood pressure. These oxylipins are known to have vascular tone-regulating properties and thus likely explain their relationship to hypertension. Plasma HDoHEs, which are oxidative products of DHA, were elevated in hypertensive patients. It was suggested that these oxylipins may have been elevated during hypertension in response to an increase in oxidative stress (27). Dietary flaxseed resulted in a decrease in plasma levels of 16-HETE, DiHETrE, and HDoHEs. However, the changes in central or brachial blood pressure induced by supplementing the diet with flaxseed were not associated with any alterations in cardiac contractile function or arterial stiffness. Thus, although ALA-derived oxylipins appear to play a role in protection from some aspects of cardiovascular disease, further delineation of its functions is required.

Oxylipins in Aging

Inflammation, oxidative stress, and vascular constriction are thought to be the causative processes of both cardiovascular disease and age-related degeneration (195). As a result, it is not surprising that the number one cause of death among older adults is cardiovascular disease. Because oxylipins influence and regulate these processes, they are important targets in aging research. AA and LA have been shown to contribute most to vasoconstriction, inflammation, oxidative stress, and tissue damage (62, 68, 105, 175, 207). Although there is growing literature on the effects of oxylipins associated with neuroinflammation and associated brain disorders such as Alzheimer’s disease (43), there is less information on the role of oxylipins in normal aging, especially in humans. For select examples of oxylipins in aging, see Table 2.

Table 2. Select oxylipins and physiological/pathophysiological effects associated with aging

OxylipinPhysiological/Pathophysiological Effect
Linoleic acid
9,10-DiHOME9,10-DiHOME is formed via the CYP epoxygenase pathway. 9,10-DiHOME levels are higher in the brain cortex of the SAMP8 model of accelerated senescence (37).
9,10,13-TriHOME TriHOMEs are produced via sequential LOX and CYP activity.
9,12,13-TriHOME9,10,13-TriHOME and 9,12,13-TriHOME were higher in plasma of 45- to 64-yr-old vs. 19- to 28-yr-old healthy men and women (23).
Arachidonic acid
PGD2PGD2 is produced via the COX pathway. Binding capacity of PGD2 to synaptic membranes decreases with age in Wistar rats (93).
PGE2PGE2 is produced via the COX pathway.
PGE2 production is higher in stimulated splenocytes and peritoneal macrophages obtained from 24- vs. 4-mo-old C57BL/6NIA mice and in stimulated splenocytes from similarly aged DBA mice (74).
Blood PGE2 is elevated in 24- vs. 6-mo-old Fischer-344 rats (95) but not in aging C57BL/6NNia mice (142).
PGE2 production in the rat liver decreases after 72 wk of age (125).
PGE2 levels are higher in the brain cortex of the SAMP8 model of accelerated senescence (37).
Ex vivo lung production of PGE2 is elevated in 24- vs. 3-mo-old mice (120).
6-keto-PGF1α6-Keto-PGF1α is the stable metabolite of PGI2 that is produced via the COX pathway.
6-Keto-PGF1α levels are lower, and production in response to thrombin is less in cultured rat aortic endothelial cells derived from 100- vs. 6-wk-old Wistar rats (128).
PGI2-mediated responses to forskolin and isoproterenol are reduced in isolated aortic rings obtained from old compared with younger Wistar-Kyoto rats (67).
6-Keto-PGF1α in the serum and aorta is elevated in 24- vs. 6-mo-old rats (95).
6-Keto-PGF1α levels are higher in the hippocampus of 18- and 24- vs. 3-mo-old rats (115).
PGF2αPGF2α is produced via the COX pathway. It causes greater ACh-stimulated contractions and vascular sensitivity in aortas from aged (18 mo) compared with young (3 mo) hamsters.
PGF2α production in the rat liver decreases after 72 wk of age (125).
PGF2α and PGE2 levels are lower in the stomach and duodenum of older (>50 yr) compared with younger (<40 yr) people (36). PGF2α is elevated in peritoneal lavages of old (20 mo) compared with young (2 mo) rats (5).
TXB2TXB2 is the stable metabolite of TXA2 produced via the COX pathway. Hippocampus and cerebral cortex TXB2 levels are higher in older (24 and 30 mo) compared with young (3−4 mo) rats (4, 115).
TXB2 in the serum and aorta are elevated in 24- vs. 6-mo-old rats (95).
TXB2 levels are higher in the brain cortex of the SAMP8 model of accelerated senescence (37). These mice also exhibit enhanced aorta contraction when exposed to a TXA2 analog, which increases with aging (135).
Arteries in aged rats with spontaneous hypertension demonstrate greater reactivity associated with TXA2 and other COX products (56, 98). TXB2 production from the lung ex vivo is elevated in 24- vs. 3-mo-old mice (120).
2,3-dinor TXB2
2,3-dinor-6-keto-PGF1α		2,3-Dinor TXB2 and 2,3-dinor-6-keto-PGF1α are urinary metabolites of TXB2 and 6-keto-PGF1α.
2,3-Dinor TXB2 and 2,3-dinor-6-keto-PGF1α, along with their parent compounds, are elevated in the urine of older (78−94 yr) compared with young (25−35 yr) individuals (203).
LTB4
LTC4		LTB4 and LTC4 are produced via the LOX pathway and are higher in stimulated splenocytes obtained from 24- compared with 4-mo-old mice (74).
LTB4 is elevated in peritoneal lavages of old (20-mo) compared with young (2 mo) rats (5).
5-HETE5-HETE is produced via the LOX pathway. Plasma levels of 5-HETE were higher in plasma of 45- to 64-yr-old vs. 19- to 28-yr-old healthy males and females (23).
12-HETE12-HETE is produced via the LOX pathway.
12-HETE-induced migration rate of aortic smooth muscle cells is higher in tissue from 25- compared with 2-mo-old rats (130).
LXA4LXA4 is produced via the LOX pathway and is involved in the resolution of inflammation.
LXA4 is inversely correlated with age in urine from 26- to 105-yr-old men and women (60).
LXB4LXB4 is produced via the LOX pathway and is involved in the resolution of inflammation. LXB4 levels were lower in peritoneal lavages of old (20 mo) compared with young (2 mo) rats (5).
14,15-EpETrEEpETrEs are produced via the CYP epoxygenase pathway and exhibit vasodilatory effects.
In rat mesenteric arteries, the vasodilatory response is reduced in response to 14,15-EpETrE in normotensive older rats (215).
19-HETE
20-HETE		19-HETE and 20-HETE are produced via the CYP ω-hydroxylase pathway.
20-HETE appears to be a greater contributor to α1-adrenergic vasoconstriction in systemic arteries of aging rats (13).
20-HETE levels were lower in the brain cortex of the SAMP8 model of accelerated senescence (37).
Eicosapentaenoic acid
5-HEPE5-HEPE is produced via the LOX pathway.
5-HEPE levels are higher in plasma of 45- to 64-yr-old vs. 19- to 28-yr-old healthy men and women (23).
Docosahexaenoic acid
11-HdoHEHDoHE is produced via the LOX pathway. Plasma levels of 11-HDoHE were higher in plasma of 45- to 64-yr-old vs. 19- to 28-yr-old healthy men and women (23).
11-HDoHE levels are lower in the brain cortex of the SAMP8 model of accelerated senescence (37).
14-HdoHE14-HDoHE is produced via the LOX pathway.
14-HDoHE levels are lower in the brain cortex of the SAMP8 model of accelerated senescence (37).
20-HdoHEHDoHE is produced via the CYP ω-hydroxylase pathway.
20-HDoHE levels are lower in the brain cortex of the SAMP8 model of accelerated senescence (37).
PD1PD1 (also known as neuroprotectin D1) is produced via the LOX pathway and is a proresolving mediator. Brain PD1-like metabolites are higher in 24- vs. 3-mo-old female NMRI mice (3).
MaR1
RvD1		MaR and Rv belong to a class of proresolving mediators that are produced via the LOX pathway from 14-HDoHE and 17-HDoHE, respectively.
MaR1 and RvD1 levels are lower in peritoneal lavages of old (20 mo) compared with young (2 mo) rats (5).

DiHOME, dihydroxy-octadecenoic acid; CYP, cytochrome P-450; SAMP8, senescence-accelerated prone mouse; TriHOME, trihydroxy-octadecenoic acid; COX, cyclooxygenase; TX, thromboxane; LT, leukotriene; LOX, lipoxygenase; EpETrE, epoxy-eicosatrienoic acid; HETE, hydroxy-eicosatetraenoic acid; HEPE, hydroxy-eicosapentaenoic acid; HDoHE, hydroxy-docosahexaenoic acid; PD, protectin; MaR, maresin; Rv, resolvin.

In humans, the expression of several genes associated with oxylipin formation, such as several PLA2 and LOX isoforms, increases with aging in human brain (158). A study on the postmortem frontal cortex found elevated levels of two PLA2 isoforms [sPLA2(IIA) mRNA and iPLA2(VIA) protein] and CYP mRNA and protein in brains from older subjects, suggesting that oxylipin levels could differ in 41- versus 70-yr-old patients (94). In a recent report, the plasma oxylipin profile in younger (19–28 yr old) versus older (45–64 yr old) healthy men and women was shown to be different (23). Thirteen oxylipins were twofold or greater in older subjects than in younger subjects. Included in these were the more proinflammatory oxylipins 5-HETE, 9,10,13-TriHOME, and 9,12,13-TriHOME as well as the ω-3-derived oxylipins 5-HEPE and 11-HDoHE, which also were significantly higher in plasma of the older group compared with the younger group (23). Diet at baseline, in particular the intake of polyunsaturated fatty acids, was not significantly different among the two groups, nor was the presence of disease, medications, or body mass index. In muscle, PGE synthase levels are higher, whereas PGE receptor (EP) levels are lower in 79-yr-old compared with 25-yr-old men and women, indicating potential differences in PGE2 effects in muscle (112). Levels of PGF2α and PGE2 are lower in the stomach and duodenum of older (>50 yr) compared with younger (<40 yr) subjects (36). TXB2 and 6-keto-PGF1α and their metabolites, 2,3-dinor TXB2 and 2,3-dinor-6-keto-PGF1α, are elevated in the urine of older (78–94 yr) compared with young (25–35 yr) individuals (204), whereas LXA4 levels are lower in older men and women (59). Thus, several studies in humans have demonstrated differences in oxylipin levels in blood, muscle, the gastrointestinal tract, and urine in older subjects.

In animal studies, the brain has been examined for oxylipin changes in aging. In the brain cortex of the senescence-accelerated prone mouse (SAMP8) model of accelerated senescence, several alterations were observed with aging, including higher levels of COX-derived AA oxylipins (PGE2 and TXB2) and the CYP-derived LA oxylipin 9,10-DiHOME and lower levels of the CYP-derived AA oxylipin 20-HETE and several LOX-derived DHA oxylipins (11-, 14-, and 20-HDoHE) (37). Other studies have indicated that increased brain 5-LOX is associated with aging (115, 149, 197). Other studies of oxylipins in brain have also reported higher levels of TXB2 and 6-keto-PGF1α in the rat hippocampus and cerebral cortex (4, 116) and higher levels of brain PD1-like metabolites in older mice (3). Whether these changes in oxylipins are associated with increased pathology or are protective against age-related degeneration remains to be determined.

The vasculature is another tissue that appears to have age-related changes in function associated with oxylipins. SAMP8 mice exhibit enhanced aorta contraction when exposed to a TXA2 analog, and this effect increases with aging (136). Serum and aorta levels of TXB2 are elevated in older rats (96), as is the expression of COX isoforms in the aorta and mesenteric arteries (118). In hamsters, PGF2α causes greater contractions and vascular sensitivity in aortas exposed to acetylcholine in older compared with younger animals (214). 12-HETE induces higher rates of migration of aortic smooth muscle cells from older rats, and 20-HETE increases α1-adrenergic vasoconstriction in older rat systemic arteries (13). On the other hand, rat aortic endothelial cells produce less of the vasodilatory 6-keto-PGF1α when derived from older rats (67, 129), but serum and aorta levels were higher in older rats in another study (96). In rat mesenteric arteries, the vasodilatory response and expression of EP2 receptors were reduced in response to 14,15-EpETrE in normotensive older rats (216), whereas arteries in aged rats with spontaneous hypertension demonstrate greater reactivity associated with TXA2 and other COX products (56, 99). Based on human cell culture studies, increasing 11,12-EpETrE with the use of sEH inhibitors has been proposed as a potential treatment of endothelial dysfunction associated with aging, an important component of cardiovascular disease (186). On the other hand, another study in aging mice found few changes in plasma CYP oxylipins, although there were some changes in CYP expression in the kidney, liver, and aorta (108). Therefore, in many, but not all, studies, oxylipin changes in aging appear to be associated with decreased functionality, raising the possibility that manipulation of oxylipin levels may be a strategy for counteracting aging effects of the vasculature.

Besides the brain and vasculature, fewer studies in other tissues in aging have been studied. Splenocyte and macrophage production of PGE2, LTB4, and LTC4 are elevated in response to stimulation in older mice (75), and peritoneal lavages from older mice have higher levels of PGF2α and LTB4 and lower levels of the proresolving LXB4, MaR1, and RvD1 (5), providing a potential link between aging and inflammation involving oxylipins. In the kidney, increased 19- and 20-HETE generation in cortex homogenates from older rats has been observed (140), and a decrease in renal PGI2 biosynthesis and renal 15-hydroxy-prostaglandin dehydrogenase activity in aging has been suggested as a potential factor in the progressive decrease in renal functions in the elderly (31). PGE2 and PGF2α also decrease in the rat liver after 72 wk of age (126), whereas ex vivo lung production of TXB2 and PGE2 was elevated in 24- compared with 3-mo-old mice (121). The implications of these age-related changes in these tissues remain to be investigated.

Nutritional Interventions Altering Oxylipins in Aging

It is possible that the oxylipin profile changes observed in aging may be modified through dietary intervention. After 4 wk of daily supplementation with 30 g of milled flaxseed, the oxylipin profile became less inflammatory in both younger and older groups, but the improvement in the older group was greater (23). In another study, EPA and DHA supplementation decreased plasma 5-HETE in younger and older healthy men (224). In aged rats, supplementation with EPA and DHA resulted in higher levels of oxylipins derived from these fatty acids and lower levels of AA-derived oxylipins, changes that were associated with improved reference memory-related learning ability (73). In contrast to ω-3 fatty acid supplementation, providing 21-mo-old Wistar rats with dietary AA had the opposite effects on renal oxylipins, which may increase the inflammatory state, although no adverse reactions under normal conditions were observed (90). Despite these interesting initial results from this small number of reports, larger dietary studies of aging populations are required before conclusions regarding the roles of dietary manipulation of oxylipins in aging can be reached. Dietary improvements and modifications even in very old age are possible and should be implemented to reduce inflammation and risk of cardiovascular disease. In the longest running longitudinal study in Canada, dietary improvements were observed in those around 85 yr old, and this was associated with better mental and physical functional scores and successful aging (25). The exact quantities and ratios of polyunsaturated fatty acids necessary to create the ideal oxylipin profile for aging and prevention of cardiovascular disease has yet to be identified. However, for older adults, the addition of ω-3 fatty acids is strongly supported for the prevention of cardiovascular disease and may aid in slowing age-related inflammation.

Summary and Future Directions

In conclusion, the effect of dietary ω-3 fatty acids on the production of oxylipins plays an important role in the mechanisms by which these dietary fatty acids reduce cardiovascular risk. Recent findings of dietary ALA effects on oxylipins in hypertensive patients suggest that this ω-3 fatty acid also may affect cardiovascular risk via unique effects on oxylipins. Fewer studies on the role of oxylipins in aging have been done, but they do implicate oxylipins in the aging process. These also are potentially altered by dietary fatty acids, but more studies are needed to continue to delineate the roles of oxylipins in age-related changes. Given the diverse functions and potencies of the different oxylipins and those derived from different fatty acids, comprehensive profiling of oxylipins in multiple tissues is necessary to appreciate the overall biological effects of the balance of these bioactive lipids. In this regard, studies comparing the biological effects of individual and combined oxylipins in multiple organ systems will enhance understanding of oxylipin functions in whole organisms. In particular, future discoveries on the effects of the oxylipins derived from LA and ALA, which make up the bulk of oxylipins in most tissues, will lead to a greater understanding of their effects in cardiovascular diseases and aging.

GRANTS

This work was supported by grants from the Advanced Rural Development Initiative, Natural Sciences and Engineering Research Council, and Canadian Institutes of Health Research (to H. Aukema) and grants from the Advanced Rural Development Initiative, Saskatchewan Flax Development Commission, Western Grains Research Foundation, and Canadian Institutes of Health Research (to G. Pierce).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

S.P.B.C. and G.N.P. conceived and designed research; S.P.B.C. analyzed data; S.P.B.C., M.P., A.S., G.N.P., and H.M.A. drafted manuscript; S.P.B.C., G.N.P., and H.M.A. edited and revised manuscript; G.N.P. prepared figures; G.N.P. and H.M.A. approved final version of manuscript.

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AUTHOR NOTES

  • Address for reprint requests and other correspondence: H. M. Aukema, Albrechtsen Research Centre, St Boniface Hospital, 351 Taché Ave., Winnipeg, MB, Canada R2H 2A6 (e-mail: ).
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