Human macrophage-mediated oxidation of low-density lipoprotein is delayed and independent of superoxide production

Garner, Brett; Dean, Roger T.; Jessup, Wendy

doi:10.1042/bj3010421

Cited by 50 publications

(30 citation statements)

References 42 publications

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“…However, at physiological pH only a fraction of O 2 Ϫ ⅐ produced is present as HO 2 ⅐. This suggests that O 2 Ϫ ⅐-generating systems, including NAD(P)H oxidases, are by themselves not efficient in oxidizing LDL (48), a notion confirmed experimentally for macrophages (289,448), although superoxide has been proposed as a mediator of LDL oxidation by endothelial cells (883). However, O 2 Ϫ ⅐ may act as the precursor for chemically more reactive oxidants, such as ONOO Ϫ and H 2 O 2 and oxidants derived from them, and these may participate in LDL oxidation in the vessel wall.…”

Section: Putative Oxidants Involvedmentioning

confidence: 97%

Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

2,244

1,756

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This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an “oxidative response to inflammation” model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

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Section: Putative Oxidants Involvedmentioning

confidence: 97%

Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

2,244

1,756

View full text Add to dashboard Cite

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“…Human monocytes ( Ͼ 95% pure by nonspecific esterase staining) were isolated by centrifugal elutriation from fresh white blood cell concentrates and plated at 1.5-2.0 ϫ 10 6 cells per 22 mm-diameter culture dish in RPMI-1640 media containing penicillin and streptomycin (50 U/ml and 50 g/ml, respectively) at 37 Њ C as described (14,32,33). Monocytes were incubated for an initial 1.5 h to establish adherence, and then the medium was exchanged with fresh RPMI-1640-containing 10% heat-inactivated whole human serum.…”

Section: Culture and Loading Of Cellsmentioning

confidence: 99%

Cyclodextrins differentially mobilize free and esterified cholesterol from primary human foam cell macrophages

Liu

Cogny

Kockx

et al. 2003

Journal of Lipid Research

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“…Monocytes were removed by density gradient separation and counterflow centrifugation elutriation. 8 Monocyte purity was Ͼ90% and viability Ͼ95% (trypan blue) in all experiments. …”

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confidence: 99%

Androgen Receptor Expression Is Greater in Macrophages From Male Than From Female Donors

et al. 2000

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Background-Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. Methods and Results-Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (nϭ8) and premenopausal female-donor (nϭ8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64Ϯ0.06 versus 0.15Ϯ0.02 amol/g total RNA; PϽ0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (Pϭ0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (nϭ9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109Ϯ10%, 117Ϯ3%, and 120Ϯ4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, Pϭ0.002; 95Ϯ8% for DHT with hydroxyflutamide, Pϭ0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (PϾ0.2 versus controls). Conclusions-Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men. en have an earlier onset and higher incidence of atherosclerosis than women. 1 The potential protective effects of estrogens on vascular structure and function have been studied extensively. Much less work, however, has addressed the possible effects of androgens on atherogenesis. In animal models, androgen treatment may increase plaque formation in the aorta and coronary vessels. 2,3 Furthermore, in humans, we have recently demonstrated that androgens enhance monocyte adhesion to endothelial cells 4 and are associated with impaired vascular reactivity. 5 Foam cell formation is a key early event in atherosclerosis and is largely due to the uptake of modified lipoproteins, principally LDL, by peripheral blood monocyte-derived macrophages (MDMs) in the arterial wall. 6,7 The possibility that androgen receptors (ARs) and androgen-related intracellular pathways may be involved in the process of lipid loading and foam cell formation in atherosclerosis has not been explored previously. We therefore investigated whether the AR is expressed in primary human MDMs and whether there is a sex difference in its expression and have examined the biological effects of androgen stimulation on cholesteryl ester (CE) formation/lipid loading in these cells. Methods Isolation of Human MonocytesWhite cell concentrates (Red Cross Blood Bank) were obtained from the peripheral blood of individual healthy men (20 to 58 years old) and premenopausal (18 to 45 years old) and postmenopausal (45, 55, and 72 years old) women. The postmenopau...

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Human macrophage-mediated oxidation of low-density lipoprotein is delayed and independent of superoxide production

Cited by 50 publications

References 42 publications

Role of Oxidative Modifications in Atherosclerosis

Role of Oxidative Modifications in Atherosclerosis

Cyclodextrins differentially mobilize free and esterified cholesterol from primary human foam cell macrophages

Androgen Receptor Expression Is Greater in Macrophages From Male Than From Female Donors

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