Discovery of lipid peroxidation products formed
            <i>in vivo</i>
            with a substituted tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension

Fessel, Joshua P.; Porter, Ned A.; Moore, Kevin; Sheller, James R.; Roberts, L. Jackson

doi:10.1073/pnas.252649099

Cited by 208 publications

(183 citation statements)

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“…IsoFs are recently described products of the same pathway whose formation is favored over IsoPs under conditions of increased oxygen tension, such as cell culture experiments and ex vivo oxidation, as occurred in the experiments described here. 21 LDL oxidation displayed the expected sequence of well-described changes. 26 DiIoxLDL was oxidized under three different conditions that yielded increasingly damaged LDL, as evidenced by consumption of ␣-tocopherol, increase in F 2 -IsoPs and IsoFs, and degradation of apoB immunoreactivity.…”

Section: Resultsmentioning

confidence: 85%

“…20,21 Samples were homogenized using a Brinkmann polytron motorized tissue grinder, and lipids were extracted using the Folch method (chloroform:methanol 2:1 v/v) supplemented with 0.005% (w/v) butylated hydroxytoluene to prevent auto-oxidation. After evaporation to dryness under nitrogen, lipids were hydrolyzed with 15% (w/v) potassium hydroxide to release esterified F 2 -IsoPs and IsoFs, and the internal standard [ 2 H 4 ]15-F 2t -IsoP added to the samples.…”

Section: Quantification Of F 2 -Isoprostanes and Isofuransmentioning

confidence: 99%

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Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Shie

Neely

Maezawa

et al. 2004

The American Journal of Pathology

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Ischemic injury to brain is associated with both disruption of the blood-brain barrier and increased oxidative stress. Given the neurotoxicity associated with exposure to oxidized low-density lipoprotein (oxLDL) in vitro, we tested the hypothesis that oxLDL may be present in parenchymal cells of cerebrum after infarction and that oxLDL may influence the pathophysiology of cerebral infarction. Our results showed that the subacute phase of cerebral infarction in patients was characterized by the appearance of oxLDL epitopes in astrocytes, but not neurons or microglia, in the perinecrotic zone. We further demonstrated that minimally oxLDL was most effectively internalized by primary cultures of rat astrocytes, and that exposure to minimal oxLDL stimulated astrocyte interleukin-6 secretion but did not alter nitric oxide production. These results demonstrate for the first time that oxLDL is present in brain parenchyma of patients with ischemic infarction and suggest a potential mechanism by which oxLDL may activate innate immunity and thereby indirectly influence neuronal survival. Lipoproteins are complex structures that orchestrate lipid trafficking through direct interaction with cell membranes and through receptor-mediated processes with apolipoproteins. Low-density lipoprotein (LDL) and its major apolipoprotein, apoB, are prone to oxidation in circulation and the resultant oxidized (ox)LDL is thought to be a key element in atherogenesis.1 Increasing evidence shows that oxLDL is internalized by or activates cell-surface receptors on endothelial cells, vascular smooth muscle cells, and monocytes/macrophages, and thereby alters several cellular functions that can culminate in cell death.2 Indeed, oxLDL is cytotoxic to many cell types in culture primarily through these receptor-dependent processes. Importantly, the pathophysiology of oxLDL is much more complicated than simply inducing death in cultured cells; oxLDL also affects leukocyte adhesion, motility of various cell types, growth factor production, and activation of innate immunity. In our original description of central nervous system (CNS) lipoproteins from patients with Alzheimer's disease (AD), we detected disease-related changes in lipids that are consistent with increased oxidation of CNS lipoproteins compared to age-matched controls. 4 We subsequently demonstrated that minimally oxidized human cerebrospinal fluid lipoproteins are toxic to cultured neurons, establishing that oxidation of lipoproteins normally residing in the CNS is capable of inducing neuron cell death in culture. 5,6 Similarly, others have demonstrated neuronal cytotoxicity from oxLDL. Specifically, oxLDL mediates time-and dose-dependent cytotoxicity to primary cultures of embryonic rodent cerebral and hippocampal neurons but not astrocytes or microglia. 7,8 Unlike experiments with minimally oxidized cerebrospinal fluid lipoproteins, these experiments with oxLDL did not include characterizing the extent of LDL oxidation, a variable known to significantly impact biological activity.The C...

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Section: Resultsmentioning

confidence: 85%

Section: Quantification Of F 2 -Isoprostanes and Isofuransmentioning

confidence: 99%

Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Shie

Neely

Maezawa

et al. 2004

The American Journal of Pathology

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“…Bicyclic endoperoxides (1a), monocyclic peroxides (1b), and serial cyclic peroxides (1c) have previously been characterized from the mixture of products formed in the autoxidation of cholesteryl arachidonate (8,12,13). Oxidation products having a tetrahydrofuran moiety (1d) were recently characterized under conditions of reaction having increased oxygen tension (14). The epoxyisoprostanes (1e) and epoxycyclopentenones (1f) are probably derived from the bicyclic endoperoxides (15,16).…”

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confidence: 99%

Identification of a Novel Class of Endoperoxides from Arachidonate Autoxidation

Yin

Morrow

Porter

2004

Journal of Biological Chemistry

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Free radical-initiated lipid autoxidation in low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. Oxidation of the lipid components of LDL leads to a complex mixture of hydroperoxides, bicyclic endoperoxides, monocyclic peroxides, and serial cyclic peroxides. The oxidation compounds and/or their decomposition products can modify protein components, which may lead to various diseases. A novel class of peroxides (termed dioxolane-isoprostanes) having a bicyclic endoperoxide moiety characteristic of the isoprostanes and a dioxolane peroxide functionality in the same molecule was identified in the product mixture formed from in vitro autoxidation of cholesteryl arachidonate. The same products are also detected in in vitro oxidized LDL. Various mass spectrometric techniques have been applied to characterize these new peroxides. The structure of these compounds has also been confirmed by independent synthesis. We reason, based on the free radical mechanism of the transformation, that only the 12-and 8-peroxyl radicals (those leading to 12-HPETE and 8-HPETE) of arachidonate can form these new peroxides. We also suggest that the formation of these peroxides provides a rationale to explain the fact that 5-and 15-series isoprostanes are formed in preference to 8-and 12-series. Furthermore, series of other isoprostanes, such as dioxolane A 2 , D 2 , E 2 , etc., can be derived from the dioxolane-isoprostane peroxides. These findings offer further insights into the oxidation products of arachidonate and the opportunity to study their potential biological relevance.

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“…Given the existing evidence of oxidative damage in PD, F 2 -IsoPs would be expected to increase in the SN of PD patients. However, the recent discovery of a novel series of lipid peroxidation products that contain a substituted tetrahydrofuran ring, termed isofurans (IsoFs), has shed light on a potential limitation of using F 2 -IsoPs as an index of oxidant injury in settings of elevated oxygen tension (Fessel et al 2002). IsoF formation is increasingly favored with increasing oxygen tension in vitro and in vivo.…”

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confidence: 99%

Isofurans, but not F₂‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

Fessel¹,

Hulette

Powell

et al. 2003

Journal of Neurochemistry

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F 2 -isoprostanes (F 2 -IsoPs) are well-established sensitive and specific markers of oxidative stress in vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F 2 -IsoPs, their formation is favored when oxygen tension is increased in vitro or in vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F 2 -IsoPs and IsoFs. In this study, we attempted to compare the levels of F 2 -IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age-matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F 2 -IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F 2 -IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age-matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.

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Discovery of lipid peroxidation products formed in vivo with a substituted tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension

Cited by 208 publications

References 28 publications

Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Identification of a Novel Class of Endoperoxides from Arachidonate Autoxidation

Isofurans, but not F₂‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

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Discovery of lipid peroxidation products formed in vivo with a substituted tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension

Cited by 208 publications

References 28 publications

Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

Identification of a Novel Class of Endoperoxides from Arachidonate Autoxidation

Isofurans, but not F2‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

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Isofurans, but not F₂‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease