Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro

Podrez, Eugene A.; Schmitt, David; Hoff, Hans; Hazen, Stanley L.

doi:10.1172/jci5549

Cited by 446 publications

(330 citation statements)

References 72 publications

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“…The process of nitration involves radicalar mechanisms, in which an electron derived from peroxynitrite attacks the aromatic ring of tyrosine, leading to the formation of a tyrosyl radical, which rapidly combines with nitrogen dioxide ( • NO 2 ) to form 3-nitrotyrosine. In addition to peroxynitrite, another nitration path is the H 2 O 2 /NO 2 -/myeloperoxidase system, which uses nitrite derived from nitric oxide for nitration 39 . 17β-estradiol has been shown to block the induction of formation of peroxynitrite in cell culture 40 .…”

Section: Discussionmentioning

confidence: 99%

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

Pereira

Bertolami

Faludi

et al. 2003

Arq. Bras. Cardiol.

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Original ArticleCardiovascular diseases are less prevalent in premenopausal women and in those receiving hormone replacement therapy as compared with postmenopausal women and men 1 . This protective effect is attributed to estrogens, and one of the mechanisms of action may be related to the metabolism of plasma lipoproteins 2 .Estrogens reduce LDL-cholesterol and increase HDLcholesterol 3 . However, these changes in lipid profile only contribute to approximately 25% of the protective effect of estrogens 4 . Other potential mechanisms of action of estrogens may include protection against LDL oxidation 5 , reduction in lipoprotein(a), potentiation of fibrinolysis 6 , and increase in insulin sensitivity. In the arteries, estrogens improve vasodilating function, decrease calcification, secretion of cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and formation of atherosclerotic lesions 7 .Direct action of estrogens on the arterial wall has also been demonstrated. The administration of estrogens for prolonged periods inhibits the deposition of cholesterol in the arteries and thickening of the intima in monkeys and rabbits fed an atherogenic diet 8 . However, the mechanisms determining the direct effects of estrogens on the arterial wall have not been completely elucidated. The hemodynamic effects may be partially measured by the activity of estrogens on the synthesis of endothelial nitric oxide 9 . Estrogens have been suggested to possibly improve endothelial function and decrease the risks of atherosclerosis in premenopausal women. Nitric oxide has its bioactivity reduced in postmenopausal women. However, it is not clear whether this occurs due to its lower production by nitric oxide synthase, or whether nitric oxide is inactivated by reaction with the superoxide radical also generated by endothelial cells, forming the peroxynitrite anion (ONOO -), which is a strong oxidizing agent.Peroxynitrite is decomposed into other reactive oxygen species ( fig. 1) 10 and reacts with tyrosine residues of proteins to form nitrotyrosine 11 . Although little is known NOx, nitrotyrosine, COx, CE 18:2 -OOH, and PC-OOH were higher in the postmenopausal period (33.8±22.3 µM; 230±130 nM; 55±19 ng/µL; 17±8.7 nM; 2775±460 nM, respectively) Objective -To assess the effect of endogenous estrogens on the bioavailability of nitric oxide (·NO) and in the formation of lipid peroxidation products in pre-and postmenopausal women. Methods -NOx and S-nitrosothiols were determined by gaseous phase chemiluminescence, nitrotyrosine was determined by ELISA, COx (cholesterol oxides) by gas chromatography, and cholesteryl linoleate hydroperoxides (CE 18:2 -OOH), trilinolein (TG 18:2 -OOH), and phospholipids (PC-OOH) by HPLC in samples of plasma. Results -The concentrations of

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Section: Discussionmentioning

confidence: 99%

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

Pereira

Bertolami

Faludi

et al. 2003

Arq. Bras. Cardiol.

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“…Unlike macrophage scavenger receptor A types I and II (SR-AI/II), CD36 binds LDL that has been exposed to "minimally" oxidizing conditions. Later work by Podrez et al showed that, again in contrast to SR-AI/II, CD36 can recognize LDL modified by the myeloperoxidase-hydrogen peroxide-nitrite system of phagocytic cells (MPO-oxLDL), which may have more physiological relevance than copper-oxidized or acetylated LDL (16). The same authors have also shown that MPO-oxLDL-dependent foam cell formation can be inhibited by as much as 80% with mAb's against CD36 (17).…”

Section: Uptake Of Modified Lipoproteins: Cd36 In Atherogenesismentioning

confidence: 99%

CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism

Febbraio¹,

Hajjar²,

Silverstein³

2001

J. Clin. Invest.

1,007

828

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“…Tyrosine nitration, a post-translational modification of proteins through the addition of a nitro (NO 2 ) group in the ortho position of tyrosine residues [49], has been detected under physiological settings and in a number of pathological states including inflammatory and septic conditions [46,50,51]. Peroxynitrite reacts rather specifically with tyrosine residues in proteins leading to the formation of nitrotyrosine, which in itself could be toxic, e.g., by undergoing redox cycling, by interfering with signal transduction, or by becoming incorporated into the microtubules protein tubulin and distorting the cytoskeleton [52].…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol reverses shear-stress-mediated low density lipoprotein modifications

Hwang¹,

Rouhanizadeh²,

Hamilton³

et al. 2006

Free Radical Biology and Medicine

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Within arterial bifurcations or branching points, oscillatory shear stress (OSS) induces oxidative stress mainly via the NADPH oxidase system. It is unknown whether 17β-estradiol (E 2 ) can regulate OSS-mediated low density lipoprotein (LDL) modifications. Bovine aortic endothelial cells (BAECs) were pre-treated with E 2 at 5 nmol/L, followed by exposure to OSS (0 ± 3.0 dynes/ cm 2 sec and 60 cycles/min) in a flow system. E 2 decreased OSS-mediated NADPH oxidase mRNA expression, and E 2 -mediated ·NO production was mitigated by the ·NO synthase inhibitor L-NAME. The rates of O 2 −· production in response to OSS increased steadily as determined by superoxide dismutase-inhibited ferricytochrome c reduction; however, pre-treatment with E 2 decreased OSS-mediated O 2 −· production (n=4, P<0.05). In the presence of native LDL (50 μg/ mL), E 2 also significantly reversed OSS-mediated LDL oxidation as determined by high performance liquid chromatography. In the presence of O 2 −· donor, xanthine oxidase (XO), E 2 further reversed XO-induced LDL lipid peroxidation (n=3, P<0.001). Mass spectra were acquired in the m/z 400-1800 range, revealing XO-mediated LDL protein nitration involving tyrosine 2535 in the α-2 domains, whereas pre-treatment with E 2 reversed this observation, consistent with the changes in nitrotyrosine intensities by the dot blots. E 2 plays an indirect antioxidative role. In addition to up-regulation of eNOS and down-regulation of Nox4 expression, E 2 influences LDL modifications via lipid peroxidation and protein nitration.

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Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro

Cited by 446 publications

References 72 publications

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism

17β-Estradiol reverses shear-stress-mediated low density lipoprotein modifications

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