Peroxynitrite modification of low‐density lipoprotein leads to recognition by the macrophage scavenger receptor

Graham, Annette; Hogg, Neil; Kalyanaraman, Balaraman; O'leary, Vanessa J.; Darley‐Usmar, Victor; Moncada, Salvador

doi:10.1016/0014-5793(93)80269-z

Cited by 274 publications

(143 citation statements)

References 46 publications

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“…Many studies have demonstrated the ability of ONOO 2 to cause oxidative modifications of the LDL components (23)(24)(25)(26)(27). ONOO 2 -modified LDL (nitrated LDL) is recognized by the macrophage scavenger receptor (28), supporting the crucial role of ONOO 2 in atherogenesis (22). LDL is generally surrounded by extrinsic antioxidants, including albumin (29).…”

Section: Discussionmentioning

confidence: 99%

“…Other considerations make these questions crucial. Protein nitration by ONOO 2 could be either deleterious, because it has been reported to enhance allergic responses (28), or beneficial because it may function as a defense mechanism against the cytotoxic action of ONOO 2 (29). Denitration could appear beneficial in the first case, and beneficial or deleterious, depending on the products released by the denitration process, in the second case.…”

Section: Discussionmentioning

confidence: 99%

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First evidence for an LDL‐ and HDL‐associated nitratase activity that denitrates albumin‐bound nitrotyrosine—Physiological consequences

Léger

Torres‐Rasgado²,

Fouret³

et al. 2007

IUBMB Life

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SummaryIn the systemic circulation, LDL occurs in the form of a weakly nitrated LDL-albumin complex (LAC). The question here is whether LAC (or HDL) is able to denitrate the albumin-bound 3-NO 2 -tyrosine (3NT). Nitrated albumin was incubated in the presence of lipoprotein fraction (LPF) to be tested, with or without Ca 21 . After precipitation and centrifugation, supernatants (SNs) and protein pellets (PP) were collected. HCl proteolysis was carried out with deuterated 3NT as an internal standard, and amino acids were derivatized for GC-MS analysis, whereas SNs were used for NO 2 2 /NO 3 2 -fluorimetric assays. A loss of 3NT, higher with albumin-low LDL than with albumin-rich LDL or HDL, was found in PP only in the presence of Ca 21 . c-Tocopherol loading of LPF inhibited 3NT loss. 3NT loss was found for the first time to be stoichiometrically equivalent to NO 3 2 , proving that the 3NT loss must be ascribed to a 3NT-denitrating nitratase activity. 3NT loss and NO 3 2 production that clearly cannot be attributed to PON-1 were impaired by D-penicillamine and phenylacetate, inhibitor, and substrate of PON-1, respectively, leading to speculate on the active site. Finally, nitratase activity and albumin contribute to beneficially convert peroxynitrite (ONOO 2 ) into nonbioactive NO 3 2 . But, in inflammatory conditions, xanthine oxidoreductase is expressed leading to detrimentally reduce O 2 and NO 3 2 into O 2 2 and NO that may interact, reconstituting the ONOO 2 pool. The real consequence of nitratase activity and the physiological significance of nitration/denitration processes remain to be explored. IUBMBIUBMB Life, 60(1): [73][74][75][76][77][78] 2008

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

First evidence for an LDL‐ and HDL‐associated nitratase activity that denitrates albumin‐bound nitrotyrosine—Physiological consequences

Léger

Torres‐Rasgado²,

Fouret³

et al. 2007

IUBMB Life

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“…Peroxynitrite, therefore, as one of the main deleterious NO-derived ROS, produces further injurious effects on the cardiovascular system, namely on several distinct vascular and platelet mechanisms, including lipid peroxidation, augmentation of platelet aggregation or modification of LDL and promotion of its pro-atherogenic interaction with macrophages. 31,32 Fig 2. Serum MDA content (A), MDA/TAS index (B), and plasma nitrotyrosine levels (C) in the 5 rat groups under study at the end of the treatments.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress in Cyclosporine-Induced Hypertension: Evidence of Beneficial Effects or Tolerance Development With Nitrate Therapy

Reis

Rocha‐Pereira

Lemos

et al. 2007

Transplantation Proceedings

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The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n ϭ 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn ϩ CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA ϩ Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn ϩ CsA therapy showed, when compared with the CsA group, total prevention of CsAinduced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA ϩ Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 Ϯ 1.4 vs 12.78 Ϯ 3.63 mol/L; P Ͻ .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.

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“…NO is a relatively stable free radical that is unable to oxidize LDL directly under physiological conditions (22,23). However, it reacts rapidly with superoxide to form peroxynitrite (ONOO Ϫ ) (24), a reactive nitrogen species that promotes peroxidation of the lipid moiety of LDL in vitro (25). Proteins also appear vulnerable to ONOO Ϫ because the oxidant reacts in vitro with tyrosine residues to yield the stable product 3-nitrotyrosine (26).…”

mentioning

confidence: 99%

Human Atherosclerotic Intima and Blood of Patients with Established Coronary Artery Disease Contain High Density Lipoprotein Damaged by Reactive Nitrogen Species

Pennathur

Bergt

Shao

et al. 2004

Journal of Biological Chemistry

255

230

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High density lipoprotein (HDL) is the major carrier of lipid hydroperoxides in plasma, but itis not yet established whether HDL proteins are damaged by reactive nitrogen species in the circulation or artery wall. One pathway that generates such species involves myeloperoxidase (MPO), a major constituent of artery wall macrophages. Another pathway involves peroxynitrite, a potent oxidant generated in the reaction of nitric oxide with superoxide. Both MPO and peroxynitrite produce 3-nitrotyrosine in vitro. To investigate the involvement of reactive nitrogen species in atherogenesis, we quantified 3-nitrotyrosine levels in HDL in vivo. The mean level of 3-nitrotyrosine in HDL isolated from human aortic atherosclerotic intima was 6-fold higher (619 ؎ 178 mol/mol Tyr) than that in circulating HDL (104 ؎ 11 mol/mol Tyr; p < 0.01). Immunohistochemical studies demonstrated striking colocalization of MPO with epitopes reactive with an antibody to 3-nitrotyrosine. However, there was no significant correlation between the levels of 3-chlorotyrosine, a specific product of MPO, and those of 3-nitrotyrosine in lesion HDL. We also detected 3-nitrotyrosine in circulating HDL, and linear regression analysis demonstrated a strong correlation between the levels of 3-chlorotyrosine and levels of 3-nitrotyrosine. These observations suggest that MPO promotes the formation of 3-chlorotyrosine and 3-nitrotyrosine in circulating HDL but that other pathways also produce 3-nitrotyrosine in atherosclerotic tissue. Levels of HDL isolated from plasma of patients with established coronary artery disease contained twice as much 3-nitrotyrosine as HDL from plasma of healthy subjects, suggesting that nitrated HDL might be a marker for clinically significant vascular disease. The detection of 3-nitrotyrosine in HDL raises the possibility that reactive nitrogen species derived from nitric oxide might promote atherogenesis. Thus, nitrated HDL might represent a previously unsuspected link between nitrosative stress, atherosclerosis, and inflammation.

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Peroxynitrite modification of low‐density lipoprotein leads to recognition by the macrophage scavenger receptor

Cited by 274 publications

References 46 publications

First evidence for an LDL‐ and HDL‐associated nitratase activity that denitrates albumin‐bound nitrotyrosine—Physiological consequences

First evidence for an LDL‐ and HDL‐associated nitratase activity that denitrates albumin‐bound nitrotyrosine—Physiological consequences

Oxidative Stress in Cyclosporine-Induced Hypertension: Evidence of Beneficial Effects or Tolerance Development With Nitrate Therapy

Human Atherosclerotic Intima and Blood of Patients with Established Coronary Artery Disease Contain High Density Lipoprotein Damaged by Reactive Nitrogen Species

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