Oxidation of Free Fatty Acids in Low Density Lipoprotein by 15-Lipoxygenase Stimulates Nonenzymic, α-Tocopherol-mediated Peroxidation of Cholesteryl Esters

Upston, Joanne M.; Neužil, Jiřı́; Witting, Paul K.; Alleva, Renata; Stocker, Roland

doi:10.1074/jbc.272.48.30067

Cited by 63 publications

(63 citation statements)

References 43 publications

(56 reference statements)

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“…In vitro, 15-lipoxygenase can oxidize LDL (51), and this is achieved by a combination of direct, enzymatic and indirect, nonenzymatic oxidation reactions (396,965,1076). Formation of nonenzymatic oxidation products has been linked to the ability of cyclooxygenase and lipoxygenases to generate oxidants in addition to the specifically oxidized fatty acids.…”

Section: Lipoxygenasesmentioning

confidence: 99%

“…It is well known that cyclooxygenase also engages in the oxidation of other substrates (e.g., 13-cis-retinoic acid) via 1e-reactions (797), implying the generation of radicals as by-products during normal enzymatic reaction. Similarly, LOO⅐ are generated and released during the catalytic action of lipoxygenases (142) and may participate in subsequent nonenzymatic lipid peroxidation (665,964,965). In addition, thromboxane synthase cleaves prostaglandin H 2 to 12-hydroxy-5,8,10-heptadecanoic acid and produces malonyldialdehyde.…”

Section: Lipoxygenasesmentioning

confidence: 99%

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Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

Self Cite

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: Lipoxygenasesmentioning

confidence: 99%

Section: Lipoxygenasesmentioning

confidence: 99%

Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

Self Cite

2,244

1,756

View full text Add to dashboard Cite

show abstract

“…There is supporting evidence that lipid peroxidation may play a role in the potential anticarcinogenic effect of other breast cancer factors, including soy (28,(181)(182)(183)(184)(185)(186)(187), marine n-3 fatty acids (46), thyroid diseases (188)(189)(190)(191)(192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202), green tea (203)(204)(205)(206)(207), vitamin D (208), calcium (209)(210)(211)(212), folate (213), and isothiocyanates (214)(215)(216)(217).…”

Section: Other Suspected Protective/risk Factors For Breast Cancermentioning

confidence: 99%

Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer

Gago‐Dominguez

Castelao

Pike

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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We have recently proposed a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. Our hypothesis posits lipid peroxidation, which is a principal mechanism in rodent renal carcinogenesis, as an intermediate step that leads to a final common pathway shared by numerous observed risks (including obesity, hypertension, smoking, oophorectomy/hysterectomy, parity, preeclampsia, diabetes, and analgesics) or protective factors (including oral contraceptive use and alcohol) for renal cell cancer [Cancer Causes Control 2002;13:287 -93]. During this exercise, we have noticed how certain risk factors for renal cell carcinoma are protective for breast cancer and how certain protective factors for renal cell carcinoma increase risk for breast cancer. Parity and oophorectomy, for example, are positively associated with renal cell carcinoma but are negatively associated with breast cancer. Similarly, obesity and hypertension are positively associated with renal cell carcinoma, but obesity is negatively associated with breast cancer in premenopausal women and hypertension during pregnancy is negatively associated with breast cancer. Furthermore, alcohol intake, negatively associated with renal cell carcinoma, is also positively associated with breast cancer. We propose here the possibility that lipid peroxidation may represent a protective mechanism in breast cancer. Although this runs counter to the conventional view that lipid peroxidation is a process that is harmful and carcinogenic, we present here the chemical and biological rationale, based on epidemiologic and biochemical data, which may deserve further consideration and investigation. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2829 -39)

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“…These lipid substances are the most susceptible to oxidative modification, and they participate in free radical propagation reactions initiated during oxidant stress. The exact nature of the critically important oxidized components of LDLs, including lipids, has been the matter of considerable conjecture, with lines of evidence suggesting an important role for cholesterol ester hydroperoxides, including those derived from direct oxidation by 15-lipoxygenase, as well as oxidized products derived from glycerophospholipid components (7,8).…”

Section: Introductionmentioning

confidence: 99%

The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis

Mallat

Nakamura²,

Ohan³

et al. 1999

J. Clin. Invest.

163

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Evidence for increased oxidant stress has been reported in human atherosclerosis. However, no information is available about the importance of in situ oxidant stress in relation to plaque stability. This information is relevant because the morbidity and mortality of atherosclerosis are essentially the consequences of acute ischemic syndromes due to unstable plaques. We studied 30 carotid atherosclerotic plaques retrieved by endarterectomy from 18 asymptomatic (stable plaques) and 12 symptomatic patients (unstable plaques). Four normal arteries served as controls. After lipid extraction and ester hydrolysis, quantitation of different indices of oxidant stress were analyzed, including hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatetraenoic acids (EETs), ketoeicosatetraenoic acids (oxoETEs), and F 2 -isoprostanes using online reverse-phase high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS). All measurements were carried out in a strictly double-blind procedure. We found elevated levels of the different compounds in atherosclerotic plaques. Levels of HETEs were 24 times higher than EETs, oxo-ETEs, or F 2 -isoprostanes. Levels of HETEs, but not those of EETs, oxo-ETEs or F 2 -isoprostanes, were significantly elevated in plaques retrieved from symptomatic patients compared with those retrieved from asymptomatic patients (1,738 ± 274 vs. 1,002 ± 107 pmol/µmol lipid phosphorous, respectively; P < 0.01). One monooxygenated arachidonate species, 9-HETE, which cannot be derived from known enzymatic reactions, was the most abundant and significant compound observed in plaques, suggesting that nonenzymatic lipid peroxidation predominates in advanced atherosclerosis and may promote plaque instability.

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Oxidation of Free Fatty Acids in Low Density Lipoprotein by 15-Lipoxygenase Stimulates Nonenzymic, α-Tocopherol-mediated Peroxidation of Cholesteryl Esters

Cited by 63 publications

References 43 publications

Role of Oxidative Modifications in Atherosclerosis

Role of Oxidative Modifications in Atherosclerosis

Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer

The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis

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