Increased levels of lipid oxidation products in low density lipoproteins of patients suffering from rheumatoid arthritis

Jira, Wolfgang; Spiteller, Gerhard; Richter, Andreas

doi:10.1016/s0009-3084(97)00030-3

Cited by 74 publications

(38 citation statements)

References 40 publications

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“…Since these substances are formed in the membrane in the vicinity of TRPV1, substantially high concentrations of these substances could occur in the local microenvironment. It should be noted that in inflammatory diseases, relatively high levels of HODEs are observed even in extracellular compartments (22)(23). Our data indicate that 9-HODE and 13-HODE substantially contribute to the heat responsiveness of TRPV1 in vitro and in vivo.…”

Section: Figurementioning

confidence: 62%

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: Figurementioning

confidence: 62%

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%

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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“…Jira et al (44,45), in fact, have reported increases in HODEs in LDL in diseases associated with increased oxidative stress, such as rheumatoid arthritis (44) and atherosclerosis (45). In obese type 2 diabetic patients, plasma 9-and 13-HODE levels are decreased by troglitazone therapy (46), but no information is available regarding plasma or lipoprotein-related HODE concentrations in T1DM.…”

Section: Discussionmentioning

confidence: 99%

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Brock

Jenkins

Lyons

et al. 2008

Journal of Lipid Research

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Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q 84 -M 86 -K 88 , W 108 -M 112 -R 116 , and L 144 -M 148 -R 149 . These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met 86 , Met 112 , and Met 148 ) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N : -malondialdehyde-lysine or N : -(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.-Brock, J.

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Increased levels of lipid oxidation products in low density lipoproteins of patients suffering from rheumatoid arthritis

Cited by 74 publications

References 40 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

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

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