Structural Identification by Mass Spectrometry of Oxidized Phospholipids in Minimally Oxidized Low Density Lipoprotein That Induce Monocyte/Endothelial Interactions and Evidence for Their Presence in Vivo

Watson, Andrew D.; Leitinger, Norbert; Navab, Mohamad; Faull, Kym F.; Hörkkö, Sohvi; Witztum, Joseph L.; Palinski, Wulf; Schwenke, Dawn C.; Salomon, Robert G.; Wang, Sha; Subbanagounder, Ganesamoorthy; Fogelman, Alan M.; Berliner, Judith A.

doi:10.1074/jbc.272.21.13597

Cited by 729 publications

(813 citation statements)

References 68 publications

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“…37 Second, our observation has potential implications for the formation of both minimally modified LDL and isoprostanes. Oxovaleroyl, glutaroyl, and epoxyisoprostane (the three active moieties identified in minimally modified LDL generated in vitro 38 ) and isoprostanes are secondary lipid oxidation products. The formation of isoprostanes is essentially prevented as long as ␣-TOH is present.…”

Section: Discussionmentioning

confidence: 99%

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Upston

Niu

Brown

et al. 2002

The American Journal of Pathology

125

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Oxidative modification of low-density lipoprotein is thought to promote arterial lipid accumulation and atherogenesis. Previous studies reported on the presence of certain lipid or protein oxidation products in lesions, although a systematic investigation measuring several oxidation parameters and the accumulation of nonoxidized lipids and antioxidants at various stages of atherosclerosis has not been performed in the same tissue. Using the intimal lipoprotein-containing fraction of human aortic lesions, we demonstrate here that cholesterol accumulated with lesion development and that this increase was already significant at the fatty streak stage. By comparison, cholesterylesters increased significantly only in fibrofatty and more complex lesions that also contained significantly increased amounts of cholesterylester hydro(pero)xides and 27-hydroxycholesterol. Cholesterylester hydroxides were the major lipid oxidation product detected. Despite accumulation of oxidized lipid, ␣-tocopherol was also present and maintained at a comparable level over the disease process. Of the oxidized protein moieties measured only o,o-dityrosine increased with disease, although chlorotyrosines were present at relatively high levels in all lesions compared to healthy vessels. Our data show that accumulation of nonoxidized lipid precedes that of oxidized lipid in human aortic lesions. The development of atherosclerosis to clinical manifestations is a protracted process that spans several decades. It is well established that lipids, specifically cholesterol, accumulate as the disease progresses 1 and that these lipids are derived from plasma low-density lipoprotein (LDL). Aberrant uptake of LDL and its associated lipids by intimal monocytes that have infiltrated from the blood is believed to generate foam cells and thereby initiate atherosclerosis. 2 Foam cells are the hallmark of the fatty streak/early lesion from which the more advanced and complicated lesions derive. In advanced lesions, a fibrous cap is formed from collagen and a lipid-rich necrotic core. Vessel lumen narrowing because of the enlarged fibrous cap and plaque rupture lead to clinical manifestations.The definitive mechanisms leading to the initiation and development of atherosclerosis are unknown. However, retention of LDL in the vessel wall because of interaction and complex formation with extracellular matrix components is well-documented 3 and is thought to be important. Further, a bulk of evidence suggests that oxidative modifications to LDL contribute to its retention. 4 -6 Both arterial wall retention and oxidative modification of LDL are thought to contribute to foam cell formation.In vitro studies with plasma LDL have shown that oxidative modifications proceed in different stages and involve changes to LDL's antioxidants, lipids, and protein components. The nature and extent of these alterations vary depending on the type of oxidant involved, the oxidant to lipoprotein ratio used, and the extent to which oxidation is allowed to proceed. Originally 4 the pa...

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Section: Discussionmentioning

confidence: 99%

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Upston

Niu

Brown

et al. 2002

The American Journal of Pathology

125

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“…The extent of oxidation was monitored by positive ion flow injection electrospray mass spectrometry (49). Biologically active phospholipids, 1-palmitoyl-2-glutaryl-sn -glycero-3-phosphorylcholine (PGPC, m/z 610), 1-palmitoyl-2-(5-oxovaleryl)-sn -glycero-3-phosphorylcholine (POVPC, m/z 594), and 1-palmitoyl-2-isoprostanoyl-sn -glycero-3-phosphorylcholine (PIPPC, m/z 829), 2 in oxidized PAPC were isolated by preparative normal phase HPLC and electrospray mass spectrometry (50).…”

Section: Methodsmentioning

confidence: 99%

“…Augmentation of HO-1 induction by hemin pretreatment followed by oxidized PAPC treatment was also observed, similar to the results with CM-LDL treatment. We next examined three isolated oxidized phospholipids from oxidized PAPC which were recently shown to have biological activity (50), including the ability to activate endothelial cells to bind monocytes, to determine whether these oxidized phospholipids induce HO-1 mRNA (Fig. 6 B).…”

Section: Effect Of Ho-1 Expression On Cm-ldl-induced Monocyte Chemotamentioning

confidence: 99%

Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.

Ishikawa¹,

Navab²,

Leitinger³

et al. 1997

J. Clin. Invest.

273

188

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Heme catabolic processes produce the antioxidants biliverdin and bilirubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether heme catabolism promotes or inhibits inflammatory processes, including atherosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rate-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible role of HO in early atherosclerosis. Heme oxygenase-1 (HO-1), the inducible isoform of HO, was highly induced by mildly oxidized LDL, and augmented induction was observed with hemin pretreatment. This augmented HO-1 induction resulted in the reduction of monocyte chemotaxis in response to LDL oxidation. Conversely, inhibition of HO by a specific inhibitor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreatment with biliverdin or bilirubin, the products of HO, reduced chemotaxis. Oxidized phospholipids in the mildly oxidized LDL appear to be responsible for HO-1 induction, since oxidized but not native arachidonic acid-containing phospholipids also induced HO-1. These results suggest that HO-1 induced by mildly oxidized LDL may protect against the induction of inflammatory responses in artery wall cells through the production of the antioxidants biliverdin and bilirubin. ( J. Clin. Invest. 1997.

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“…The lipid residue was allowed to autooxidize while being exposed to air for 24 to 48 h. The extent of oxidation was monitored by electrospray ionization-mass spectrometry in the positive-ion mode [7].…”

Section: Ox-papc Preparationmentioning

confidence: 99%

“…Oxidized lipids, such as lipid hydroperoxide 13-HPODE, have been implicated in the activation of NAD(P)H oxidase to induce production of O 2 −• [4]. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC), a biologically active component of MM-LDL present in atherosclerotic lesions, is a common product of phosphatidylcholine peroxidation in MM-LDL [5][6][7][8]. Ox-PAPC is also a potent inducer of monocyte binding to endothelial cells [5,9,10].…”

Section: Introductionmentioning

confidence: 99%

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

Rouhanizadeh

Hwang

Clempus

et al. 2005

Free Radical Biology and Medicine

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Modified low-density lipoprotein (LDL) induces reactive oxygen species (ROS) production by vascular cells. It is unknown if specific oxidized components in these LDL particles such as oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) can stimulate ROS production. Bovine aortic endothelial cells (BAEC) were incubated with ox-PAPC (50 μg/ml). At 4 h, ox-PAPC significantly enhanced the rate of O 2 −• production. Pretreatment of BAEC in glucose-free Dulbecco's modified Eagle's medium plus 10 mM 2-deoxyglucose (2-DOG), the latter being an antimetabolite that blocks NADPH production by the pentose shunt, significantly reduced the rate of O 2 −• production. The intensity of NAD(P)H autofluorescence decreased by 28 ± 12% in BAEC incubated with ox-PAPC compared to untreated cells, with a further decrease in the presence of 2-DOG. Ox-PAPC also increased Nox4 mRNA expression by 2.4-fold ± 0.1 while pretreatment of BAEC with the small interfering RNA (siNox4) attenuated Nox4 RNA expression. Ox-PAPC further reduced the level of glutathione while pretreatment with apocynin (100 μM) restored the GSH level (control = 22.54 ± 0.23, GSH = 18.06 ± 0.98, apocynin = 22.55 ± 0.60,.17 ± 0.36 nmol/10 6 cells). Treatment with ox-PAPC also increased MMP-2 mRNA expression accompanied by a 1.5-fold increase in MMP-2 activity. Ox-PAPC induced vascular endothelial O 2 −• production that appears to be mediated largely by NADPH oxidase activity.

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Structural Identification by Mass Spectrometry of Oxidized Phospholipids in Minimally Oxidized Low Density Lipoprotein That Induce Monocyte/Endothelial Interactions and Evidence for Their Presence in Vivo

Cited by 729 publications

References 68 publications

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

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