Bio‐markers of lipid peroxidation in vivo: Hydroxyoctadecadienoic acid and hydroxycholesterol

Yoshida, Yasuyuki; Niki, Etsuo

doi:10.1002/biof.5520270117

Cited by 72 publications

(58 citation statements)

References 32 publications

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“…Linoleic acid is one of the most abundant fatty acids in the body and is a major component of the plasma membrane of nearly all cells. Under conditions such as inflammation, cytotoxicity, or hypotension, linoleic acid is rapidly oxidized to form biologically active metabolites such as 9-HODE and 13-HODE (14)(15)(16). Both 9-HODE and 13-HODE were released in increasing amounts from mouse skin biopsies exposed to a noxious temperature range (Figure 2, C and D).…”

Section: Resultsmentioning

confidence: 99%

Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

Patwardhan¹,

Akopian²,

Ruparel³

et al. 2010

J. Clin. Invest.

219

216

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The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9-and 13-hydroxyoctadecadienoic acid (9-and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9-and 13-HODE and their metabolites, 9-and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs. IntroductionThe TRP family of ligand-gated ion channels consists of several subgroups, including the vanilloid subfamily (transient receptor potential vanilloid [TRPV]). The first member of the subfamily to be discovered, TRPV1, is an extensively studied channel (1-5) that is expressed in a substantial proportion of pain-sensing sensory neurons, termed nociceptors. TRPV1 can be activated by a variety of endogenous lipids (including lipoxygenase and phospholipase D metabolites of arachidonic acid) and by exogenous substances such as capsaicin (the pungent compound in hot chili peppers) (6). We recently discovered that linoleic acid metabolites are synthesized in the spinal dorsal horn following the afferent barrage due to stimuli such as peripheral inflammation and constitute what we believe to be a novel, physiologically active family of endogenous TRPV1 ligands that mediates central sensitization to mechanical stimuli (7).In the periphery, TRPV1 also serves as a detector for noxious heat (> 43°C) (6), and pharmacological and gene deletion studies have shown that TRPV1 is important in inflammatory heat hyperalgesia and thermoregulation (8-9). However, the precise mechanism of heat activation of TRPV1 remains unknown. We found that endogenous TRPV1 agonists are formed on exposure of cell membranes to noxious heat. The released compounds activate TRPV1 and contribute to the thermal responsiveness of this channel.

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Section: Resultsmentioning

confidence: 99%

Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

Patwardhan¹,

Akopian²,

Ruparel³

et al. 2010

J. Clin. Invest.

219

216

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“…In contrast, the linoleic acid metabolites are well recognized to be involved in numerous neurological and non-neurological disorders (9,(24)(25)(26)(27)(28). The known receptors for these metabolites cannot explain all of their observed effects (29)(30).…”

Section: Discussionmentioning

confidence: 99%

“…Studies conducted in other tissues have demonstrated that these metabolites can be formed both enzymatically and nonenzymatically (9). In fact, calcium-dependent activation of the enzymes involved in the synthesis of these metabolites is known (18).…”

Section: Discussionmentioning

confidence: 99%

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Patwardhan¹,

Scotland

Akopian³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

196

191

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Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9-and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.inflammation ͉ pain T ransient receptor potential vanilloid 1 (TRPV1) plays a pivotal role in many pain models, leading to the development of hyperalgesia and/or allodynia (1-2). TRPV1 is expressed in the peripheral as well as central nervous systems (CNS) including several areas involved in nociceptive transmission (3). Numerous studies have demonstrated that peripheral TRPV1 is activated by noxious heat and protons and is regulated by endogenous ligands (2), contributing to peripheral mechanisms of heat hyperalgesia (4). However, TRPV1 is also expressed in the CNS, where comparatively little is known about the role of this receptor in mediating central pain mechanisms.Recent studies have used TRPV1 antagonists to evaluate the role of CNS TRPV1 in inflammatory hyperalgesia. Interestingly, the systemic/spinal administration of TRPV1 antagonists blocks inflammation-induced heat hyperalgesia, as well as mechanical allodynia (5-6). These findings were unexpected since TRPV1 is not activated by mechanical stimuli, suggesting that spinal TRPV1 activation leads to central sensitization to both thermal and mechanical stimuli (7-8). Based upon these observations, we hypothesized that the afferent barrage resulting from peripheral tissue injury leads to generation of endogenous TRPV1 ligands in the spinal cord that activate TRPV1 in the CNS resulting in central sensitization. Results Depolarization of Spinal Cord Results in the Release of EndogenousTRPV1 Ligands. To evaluate the hypothesis that endogenous TRPV1 agonists are released from spinal cord neurons, freshly isolated male rat spinal cords w...

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“…Increased lipid peroxidation has been associated with the development and progression of a number of chronic human diseases including CVD and diabetes (98)(99)(100)(101) . It damages biological membranes changing membrane fluidity and functions including receptor activity, and nutrient and ion transport.…”

Section: Effect Of N-3 Pufa On Lipid Peroxidationmentioning

confidence: 99%

Similarities and differences between the effects of EPA and DHA on markers of atherosclerosis in human subjects

Kelley

Adkins

2012

Proc. Nutr. Soc.

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We have reviewed effects of long chain (LC) n-3 PUFA on markers of atherosclerosis in human subjects with a focus on individual effects of EPA and DHA. Initial results from epidemiological studies suggested that LC n-3 PUFA from fish oils (FO) reduced incidence of CVD; those results have been confirmed in interventional studies. Dietary intervention with n-3 PUFA decreased fasting and postprandial TAG, number of remnant-like chylomicron particles, large VLDL, and total and small dense LDL particles. It increased mean size of LDL particles by increasing number of large and decreasing those of small dense particles. With some exceptions, n-3 PUFA decreased blood pressure (BP) and heart rate (HR), flow-mediated dilation (FMD) and plasma concentrations of inflammatory markers. n-3 PUFA also decreased circulating adhesion molecules and intima-media thickness (IMT) in some but not other studies. For IMT, results varied with the sex and artery being examined. EPA effects on FMD are endothelial cell dependent, while those of DHA seem to be endothelial cell independent. Individually, both EPA and DHA decreased TAG and inflammatory markers, but only DHA decreased HR, BP and number of small dense LDL particles. Results varied because of dose and duration of n-3 PUFA, EPA:DHA, health status of subjects and other reasons. Future studies are needed to determine optimal doses of EPA and DHA individually, their synergistic, additive or antagonistic effects, and to understand underlying mechanisms. In conclusion, n-3 PUFA decreased several risk factors for atherosclerosis without any serious adverse effects. TAG: LDL size and numbers: Intima-media thickness: Blood pressureAtherosclerosis comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It is a common disorder of the arteries in which fat and other substances build up in and on the walls of arteries and form hard structures called plaques (1) . The plaques can make the artery narrow and less flexible, making it harder for blood to flow. If the coronary arteries become narrow, blood flow to the heart can slow down or stop. This can cause chest pain (stable angina), shortness of breath, heart attack and other symptoms. Pieces of plaque can break off and move through the bloodstream (embolisation). This is a common cause of heart attack and stroke. Blood clots can also form around a tear (fissure) in the plaque and block blood flow. If the clot moves into an artery in the heart, lungs or brain, it can cause a stroke, heart attack or pulmonary embolism (2) . Eighty million American adults (approximately one in three) have CVD (3) . CVD is the number one cause of deaths in the US accounting for 34 % of all deaths or 2400 deaths each day. It is a major public health problem with an annual economic loss of $400 billion (3) .

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Bio‐markers of lipid peroxidation in vivo: Hydroxyoctadecadienoic acid and hydroxycholesterol

Cited by 72 publications

References 32 publications

Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Similarities and differences between the effects of EPA and DHA on markers of atherosclerosis in human subjects

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