Lipoprotein Size and Atherosclerosis Susceptibility in
 
 Apoe
 
 −/−
 and
 
 Ldlr
 
 −/−
 Mice

Véniant, Murielle M.; Withycombe, Shannon K.; Young, Stephen G.

doi:10.1161/hq1001.097780

Cited by 120 publications

(53 citation statements)

References 27 publications

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“…Although both b-VLDL and LDLs carry cholesterol in circulation, they are not equally atherogenic once deposited in the arterial intima. 23 b-VLDLs are large in size and contain more apoB-48 in postprandial state, whereas small-sized LDLs contain more apoB-100. In light of such physical and chemical differences between the two particles, one can envision that small-sized LDLs are more atherogenic because these small LDLs may enter the intima more easily and may be more susceptible to oxidation.…”

Section: Discussionmentioning

confidence: 98%

“…20,21 Studies using genetically modified animals have revealed that remnant lipoproteins and LDLs are actually different in terms of atherogenicity. 22,23 Although LPL is protective against cholesterol-diet-induced atherosclerosis in LDL receptor and apoE KO mice, 6,7 studies of these mice did not demonstrate a significant increase of small LDLs in LPL transgenic animals and thus failed to provide a clear answer about whether LPL-generated small LDLs are atherogenic.…”

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confidence: 99%

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Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Ichikawa

Kitajima

Liang

et al. 2004

Laboratory Investigation

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Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3-0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (b-VLDL, do1.006 g/ml) but concomitantly led to a significant increase of the large (d ¼ 1.02-1.04 g/ml) and small LDLs (d ¼ 1.04-1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptormediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of smallsized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Ichikawa

Kitajima

Liang

et al. 2004

Laboratory Investigation

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“…Possible explanations for the more aggressive disease in SR-uPA ϩ/0 Apoe Ϫ/Ϫ mice despite plasma cholesterol levels similar to those of SR-uPA ϩ/0 Ldlr Ϫ/Ϫ mice include the lack of apoE-mediated reverse cholesterol transport, absence of the anti-oxidant and anti-inflammatory activities of apoE, (43)(44)(45) and earlier onset hyperlipidemia in Apoe Ϫ/Ϫ mice. The increased longevity of SR-uPA ϩ/0 Ldlr Ϫ/Ϫ mice versus SR-uPA ϩ/0 Apoe Ϫ/Ϫ mice allowed us to quantify uPA-accelerated atherosclerosis over a more extended time course, providing clues to the mechanisms of uPA/Plg-accelerated atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Farris

Krishnan

et al. 2011

Journal of Biological Chemistry

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Data from clinical studies, cell culture, and animal models implicate the urokinase plasminogen activator (uPA)/uPA receptor (uPAR)/plasminogen system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/uPAR/plasminogen stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression and mice genetically deficient in uPAR to elucidate mechanisms of uPA/uPAR/plasminogen-accelerated atherosclerosis and aneurysm formation. We found that macrophage-specific uPA overexpression accelerates atherosclerosis and causes aortic root dilation in fat-fed Ldlr ؊/؊ mice (as we previously reported in Apoe ؊/؊ mice). Macrophage-expressed uPA accelerates atherosclerosis by stimulation of lesion progression rather than initiation and causes disproportionate lipid accumulation in early lesions. uPA-accelerated atherosclerosis and aortic dilation are largely, if not completely, independent of uPAR. In the absence of uPA overexpression, however, uPAR contributes modestly to both atherosclerosis and aortic dilation. Microarray studies identified S100A8 and S100A9 mRNA as the most highly up-regulated transcripts in uPA-overexpressing macrophages; up-regulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also up-regulated in the aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is up-regulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Macrophage microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm in a second animal model that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also reveal uPAR independence of these actions and implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease.Atherosclerosis and aneurysm formation are common cardiovascular diseases that have a significant impact on human health. Atherosclerosis is characterized by accumulation in the inner blood vessel wall of cellular and matrix-rich plaques that cause vessel lumen narrowing and tissue ischemia. Clinical events in patients with atherosclerosis (e.g. heart attacks and strokes) are typically caused by rupture of atherosclerotic plaques with superimposed thrombosis that occludes the vessel lumen (1). In contrast, aneurysms are abnormal expansions of a blood vessel that can lead to complete disruption of the vessel wall, causing sudden death (2). The molecular mechanisms that contribute to plaque growth, plaque rupture, and aneurysm formation are incompletely understood. Elucidation of these mechanisms should enable the development of novel, targeted therapies that improve human health.We and others (3) have hypothesized that the urokinase plasminogen activator (uPA) 6 /plasminoge...

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“…1 Despite the high correlation between apoB 100 and non-HDL-C, these parameters reflect different biological entities. 30 Thus, non-HDL cholesterol may not be an adequate surrogate for apoB 100 .…”

Section: Discussionmentioning

confidence: 99%

Multivariate Assessment of Lipid Parameters as Predictors of Coronary Heart Disease Among Postmenopausal Women

et al. 2004

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Background— Over the past decade, lipid measurements have been significantly improved and standardized. We evaluated the usefulness of multiple plasma lipid parameters in predicting coronary heart diseases (CHD) among women. Methods and Results— Among 32 826 women from the Nurses’ Health Study who provided blood samples at baseline, 234 CHD events were documented during 8 years of follow-up. In a nested study, these cases were matched to controls (1:2) for age, smoking, fasting status, and month of blood draw. We estimated the relative risk (RR) for each lipid parameter, adjusted for C-reactive protein, homocysteine, body mass index, family history, hypertension, diabetes, postmenopausal hormone use, physical activity, alcohol intake, and blood draw parameters. The RRs associated with an increase of ≈1 SD (mg/dL) were as follows: HDL cholesterol (HDL-C) (RR=0.6 [0.5 to 0.8], SD=17), apolipoprotein B 100 (apoB 100 ) (RR=1.7 [1.4 to 2.1], SD=32), LDL cholesterol (LDL-C) (RR=1.4 [1.1 to 1.7], SD=36), total cholesterol (TC) (RR=1.4 [1.1 to 1.6], SD=40), and triglycerides (RR=1.3 [1.0 to 1.5], SD=80). Among the lipid indexes, the RRs were: apoB 100 /HDL-C (RR=1.7 [1.4 to 2.1], SD=1.0), TC/HDL-C (RR=1.6 [1.3 to 1.9], SD=1.3), LDL-C/HDL-C (RR=1.5 [1.3 to 1.9], SD=1.0), and non–HDL-C (RR=1.6 [1.3 to 1.9], SD=42 mg/dL). After simultaneous control for several lipid biomarkers, HDL-C was the primary contributor of the variation in multivariate models ( P =0.01), followed by LDL-C ( P =0.01), whereas triglycerides and apoB 100 did not contribute further information. HDL-C–related ratios were the strongest contributors to predicting CHD ( P <0.0001). Conclusions— Lower levels of HDL-C may be a key discriminator of higher CHD events among postmenopausal women. HDL-C–related ratios (such as TC/HDL-C) provide a powerful predictive tool independently of other known CHD risk factors.

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Lipoprotein Size and Atherosclerosis Susceptibility in Apoe ^−/− and Ldlr ^−/− Mice

Cited by 120 publications

References 27 publications

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Multivariate Assessment of Lipid Parameters as Predictors of Coronary Heart Disease Among Postmenopausal Women

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Lipoprotein Size and Atherosclerosis Susceptibility in Apoe −/− and Ldlr −/− Mice

Cited by 120 publications

References 27 publications

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Multivariate Assessment of Lipid Parameters as Predictors of Coronary Heart Disease Among Postmenopausal Women

Contact Info

Product

Resources

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Lipoprotein Size and Atherosclerosis Susceptibility in Apoe ^−/− and Ldlr ^−/− Mice