Minimally modified low density lipoprotein is biologically active in vivo in mice.

Liao, Feng; Berliner, Judith A.; Mehrabian, Margarete; Navab, Mahamad; Demer, Linda L.; Lusis, Aldons J.; Fogelman, Alan M.

doi:10.1172/jci115261

Cited by 202 publications

(107 citation statements)

References 32 publications

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“…15,17,18 Injection of mm-LDL in animal models indicates that these bioactive effects appear to be maintained in vivo. 18,42 Therefore, it has been suggested that the generation of mm-LDL may be a very important early step in atherogenesis. Recent studies by several investigators have implicated oxidative decomposition products of lipoprotein phospholipids as possible proinflammatory agents responsible for some of the bioactivity of mm-LDL.…”

Section: Discussionmentioning

confidence: 99%

LDL Isolated From Greek Subjects on a Typical Diet or From American Subjects on an Oleate-Supplemented Diet Induces Less Monocyte Chemotaxis and Adhesion When Exposed to Oxidative Stress

Tsimikas

Philis‐Tsimikas

Alexopoulos

et al. 1999

ATVB

101

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Abstract-The mechanisms underlying the cardiovascular benefits of Mediterranean-style diets are not fully understood.The high content of monounsaturated fatty acids in Mediterranean-style diets derived from oleate-rich olive oil may be beneficial in reducing low density lipoprotein (LDL) oxidation and its subsequent development of atherogenic properties. This study sought to assess the proinflammatory potential of LDL isolated from subjects consuming a diet naturally rich in olive oil. LDL was isolated from 18 Greek, 18 American, and 11 Greek-Americans subjects, all of whom were living in the United States. Fatty acid composition and vitamin E levels of LDL were determined, as was the extent of copper-mediated LDL oxidation. LDL was also mildly oxidized by exposure to fibroblasts overexpressing 15-lipoxygenase and tested in vitro for bioactivity by determining its ability to stimulate monocyte chemotaxis and adhesion to endothelial cells. To confirm that dietary fatty acids influence the proinflammatory properties of mildly oxidized LDL, LDL was also isolated from 13 healthy American subjects after consumption of an 8-week liquid diet supplemented with either oleic (nϭ6) or linoleic (nϭ7) acid and tested for bioactivity in a similar fashion. There were no differences in the baseline lipid profiles among the Greeks, Americans, or Greek-Americans. Oleic acid content in LDL was 20% higher in the Greek compared with the American or Greek-American subjects (PϽ0.001). The extent of in vitro LDL oxidation, measured by conjugated diene formation, was lower in the Greek subjects (PϽ0.02), but there was no difference in the lag time. Induction of monocyte chemotaxis and adhesion by mildly oxidized LDL was decreased by 42% in the Greek group compared with the American subjects (PϽ0.001). There was an inverse correlation between the oleic acid content of LDL and stimulation of monocyte chemotaxis (rϭϪ0.64, PϽ0.001) and a positive correlation between the polyunsaturated fatty acid content of LDL (total linoleate and arachidonic acids levels in LDL) and stimulation of monocyte chemotaxis (rϭ0.51, PϽ0.01) in the entire cohort. There were no differences in LDL vitamin E content between the groups. In the liquid-diet groups, the oleic acid-supplemented group had a 113% higher oleic acid content in LDL and a 46% lower linoleic acid content in LDL than the linoleate-supplemented group (PϽ0.001), whereas the vitamin E content in LDL was equal in both groups. When exposed to oxidative stress, the LDL enriched in oleic acid promoted less monocyte chemotaxis (52% lower) and reduced monocyte adhesion by 77% in comparison with linoleate-enriched LDL (PϽ0.001). There was a strong, negative correlation between oleic acid LDL content and monocyte adhesion (rϭϪ0.73, PϽ0.001) and a strong, positive correlation between polyunsaturated fatty acid LDL content and monocyte adhesion (rϭ0.87, PϽ0.001). This study demonstrates that dietary enrichment of LDL with oleic acid is realistic and readily achieved by using diets currently in use in Mediter...

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Section: Discussionmentioning

confidence: 99%

LDL Isolated From Greek Subjects on a Typical Diet or From American Subjects on an Oleate-Supplemented Diet Induces Less Monocyte Chemotaxis and Adhesion When Exposed to Oxidative Stress

Tsimikas

Philis‐Tsimikas

Alexopoulos

et al. 1999

ATVB

101

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“…Alexander 45 showed that oils used in many restaurants are kept at 180°C for extended time periods, which results in the appearance of oxidized lipids. Thompson et al* 6 also performed oxidized lipid measurements and showed that oils used for deep-frying in restaurants, institutions, and armed services contained large quantities of oxidized lipids. Finally, Yagi et al 47 measured peroxides in 30 kinds of foods and found that the peroxide content could be as high as 600 nmoles/g food.…”

Section: Discussionmentioning

confidence: 99%

Oxidized lipids in the diet are a source of oxidized lipid in chylomicrons of human serum.

Staprãns

Rapp

Pan

et al. 1994

Arterioscler Thromb

170

135

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We examined whether oxidized lipids in the diet determine the levels of oxidized lipid in human postprandial serum chylomicrons. After we fed subjects control corn oil containing low quantities of oxidized lipid, the levels of conjugated dienes in the chylomicron fraction were low (9.67 ±0.92 nmol//imol triglyceride), and no thiobarbituric acid-reactive substances (TBARS) could be detected. However, when subjects were fed a highly oxidized oil, the conjugated diene content in chylomicrons was increased 4.7-fold to 46±5.63 nmo\/fimo\ triglyceride, with 0.140±0.03 nmol TBARS//imol triglyceride. When subjects were fed mediumoxidized oil, the degree of oxidation of the chylomicron lipids was moderately increased (21.86 ±2.03 nmol conjugated

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“…Chief among these is an ability to stimulate cholesterol engorgement by macrophages (2,3), which are progenitors of lipidladen foam cells found in early atherosclerotic lesions. In addition, oxidized-LDL influences the chemotactic behavior of monocytes and monocyte-derived macrophages (4,5), promotes endothelial cell damage (6,7), and induces potent mediators of cell proliferation, monocyte adherence, and platelet aggregation (8)(9)(10)(11)(12), all of which may contribute to lesion formation and growth.…”

mentioning

confidence: 99%

“…However, if the oxidant stress is sufficiently great or prolonged, these antioxidants are depleted (13)(14)(15)(16) and injury is propagated among LDL lipids with spread to the protein component through reactive lipid breakdown products (6,17). The atherogenic properties of oxidized-LDL are attributed to this extensively altered particle (1)(2)(3)(4)(5)(6)(7)17), although minimal modifications associated with the initial stages of injury also may be important (10)(11)(12).…”

mentioning

confidence: 99%

Oxidative susceptibility of low density lipoprotein subfractions is related to their ubiquinol-10 and alpha-tocopherol content.

Tribble

Berg

Motchnik

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

135

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The conjugated polyene fatty acid parinaric acid (PnA) undergoes a stoichiometric loss in fluorescence upon oxidation and can be used to directly monitor peroxidative stress within lipid environments. We evaluated the course of potentially atherogenic oxidative changes in low density lipoproteins (LDL) by monitoring the oxidation of PnA following its incorporation into buoyant (p = 1.026-1.032 g/ml) and dense (p = 1.040-1.054 g/ml) LDL subfractions. Copperinduced oxidation of LDL-associated PnA exhibited an initial lag phase followed by an increased rate of loss until depletion. Increased PnA oxidation occurred immediately after the antioxidants ubiquinol-10 and a-tocopherol were consumed but before there were marked elevations in conjugated dienes. Despite differences in sensitivity to early oxidation events, PnA oxidation and conjugated diene lag times were correlated (r = 0.582; P = 0.03), and both indicated a greater susceptibility of dense than buoyant LDL in accordance with previous reports. The greater susceptibility of PnA in dense LDL was attributed to reduced levels of ubiquinol-10 and a-tocopherol, which were =50% lower than in buoyant LDL (mol of antioxidant/mol of LDL) and together accounted for 80% of the variation in PnA oxidation lag times. These results suggest that PnA is a useful probe of LDL oxidative susceptibility and may be superior to conjugated dienes for monitoring the initial stages of LDL lipid peroxidation. Differences in oxidative susceptibility among LDL density subfractions are detected by the PnA assay and are due in large part to differences in their antioxidant content.Free-radical-mediated oxidation induces potentially atherogenic changes in low density lipoproteins (LDL) (1). Chief among these is an ability to stimulate cholesterol engorgement by macrophages (2, 3), which are progenitors of lipidladen foam cells found in early atherosclerotic lesions. In addition, oxidized-LDL influences the chemotactic behavior of monocytes and monocyte-derived macrophages (4, 5), promotes endothelial cell damage (6, 7), and induces potent mediators of cell proliferation, monocyte adherence, and platelet aggregation (8-12), all of which may contribute to lesion formation and growth.LDL oxidation is believed to proceed through initial oxidation of the fatty acyl components. The resulting lipidderived radicals are intercepted by radical scavenging antioxidants including ubiquinol-10 and a-tocopherol. However, if the oxidant stress is sufficiently great or prolonged, these antioxidants are depleted (13)(14)(15)(16) and injury is propagated among LDL lipids with spread to the protein component through reactive lipid breakdown products (6,17). The atherogenic properties of oxidized-LDL are attributed to this extensively altered particle (1)(2)(3)(4)(5)(6)(7)17), although minimal modifications associated with the initial stages of injury also may be important (10-12).As evidence has accumulated in support of a role for LDL oxidation in atherogenesis, assays of oxidative susceptibility hav...

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Minimally modified low density lipoprotein is biologically active in vivo in mice.

Abstract: Minimally modified low density lipoprotein (MM-LDL), de-

Cited by 202 publications

References 32 publications

LDL Isolated From Greek Subjects on a Typical Diet or From American Subjects on an Oleate-Supplemented Diet Induces Less Monocyte Chemotaxis and Adhesion When Exposed to Oxidative Stress

LDL Isolated From Greek Subjects on a Typical Diet or From American Subjects on an Oleate-Supplemented Diet Induces Less Monocyte Chemotaxis and Adhesion When Exposed to Oxidative Stress

Oxidized lipids in the diet are a source of oxidized lipid in chylomicrons of human serum.

Oxidative susceptibility of low density lipoprotein subfractions is related to their ubiquinol-10 and alpha-tocopherol content.

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