Proteoglycans Contribution to Association of Lp(a) and LDL With Smooth Muscle Cell Extracellular Matrix

Lundstam, Ulf; Hurt-Camejo, Eva; Olsson, Gert E.; Sartipy, Peter; Camejo, Germán; Wiklund, Olov

doi:10.1161/01.atv.19.5.1162

Cited by 46 publications

(22 citation statements)

References 49 publications

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“…The fact that apoB, apo(a), and OxPL did not necessarily uniformly colocalize suggests that the apoB and OxPL components of Lp(a) may be degraded and removed but that the apo(a) component continues to be bound to the plaque and have a longer residence time ( 38 ). It also suggests that additional and quantitatively signifi cant amounts of OxPL are formed in the vessel wall in situ and independently of those OxPL potentially carried by Lp(a).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions

Dijk

Kolodgie

Ravandi

et al. 2012

Journal of Lipid Research

143

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Oxidative pathways in the subendothelial space activate pro-infl ammatory, immunogenic, and atherogenic processes, resulting in endothelial dysfunction, plaque growth and destabilization, platelet activation, and thrombosis, ultimately leading to clinical events ( 1 ). A variety of oxidation-specifi c epitopes (OSE) are generated during oxidative modifi cation of plaque components. These epitopes are not only expressed on modifi ed lipoproteins but also on apoptotic cells and proteins in the extracellular matrix of atherosclerotic vessels ( 2 ).Extensive experimental data exists defi ning the role of oxidation in both progression and regression of atherosclerosis. Atherosclerotic lesions of hypercholesterolemic animal models, which represent primarily early and intermediate stage atherosclerosis, contain signifi cant amounts of OSE, often in proportion to plaque burden. OSE in the vessel wall of atherosclerotic animals can also be imaged with nuclear and magnetic resonance techniques using murine and human oxidation-specifi c antibodies, such as MDA2, E06, and IK17 ( 3-5 ). Dietary interventions in hypercholesterolemic animals that promote regression result in more rapid removal of OSE than apoB, which occurs prior to plaques diminishing signifi cantly in size, and is associated with markers of plaque stabilization, such Abstract The relationships between oxidation-specifi c epitopes (OSE) and lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophagerich areas, lipid pools, and the necrotic core, and they were most specifi cally associated with unstable and ruptured plaques. Specifi c OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic.

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Section: Discussionmentioning

confidence: 99%

Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions

Dijk

Kolodgie

Ravandi

et al. 2012

Journal of Lipid Research

143

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“…CSPGs are also important during cholesterol deposition and foam-cell formation in atherogenesis. 48 The function of EMR2/ CD97 expressing macrophages binding to CS in atherosclerotic lesions would be an interesting area of study. Finally, Decorin, another DS-containing PG, is markedly increased in the tumor stroma of colon cancer.…”

Section: Discussionmentioning

confidence: 99%

The epidermal growth factor–like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans

Stacey

Chang

Davies

et al. 2003

Blood

195

218

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Using multivalent protein probes, an evolutionarily conserved endogenous ligand for EMR2, a human myeloid cell-restricted EGF-TM7 receptor, was identified on the surface of a number of adherent cell lines. In addition, in situ staining of the ligand has revealed specific in vivo patterns consistent with a connective tissue distribution. The interaction is conserved across species and mediated exclusively by the largest EMR2 isoform containing 5 epidermal growth factor (EGF)-like modules. Antibody-blocking studies subsequently revealed that the fourth EGF-like module constitutes the major ligandbinding site. The largest isoform of CD97, a related EGF-TM7 molecule containing an identical EGF-like module, also binds to the putative EMR2 ligand. Through the use of mutant Chinese hamster ovary (CHO) cell lines defective in glycosaminoglycans (GAGs) biosynthesis as well as the enzymatic removal of specific cell surface GAGs, the molecular identity of the EMR2 ligand was identified as chondroitin sulfate (CS). Thus, exogenous CS GAGs blocked the EMR2-ligand interaction in a dose-dependent manner. EMR2-CS interaction is Ca 2؉ -and sulphation-dependent and results in cell attachment. This is the first report of a GAG ligand for the TM7 receptors extending the already vast repertoire of stimuli of the GPCR superfamily.

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“…54 Although the mechanisms of its atherogenicity are not fully known, the increased retentive properties of the unique apo(a) moiety likely contribute to this effect. 55,56 Whether Lp(a), once retained, is more easily modifiable into more atherogenic forms and/or otherwise is particularly potent at eliciting maladaptive responses represent areas of ongoing investigation. For example, a series of experimental and clinical studies by Tsimikas and colleagues 57,58 have shown that Lp(a) is rich in potentially atherogenic oxidized phospholipids, a property shown to be predictive of atherosclerotic vascular disease in humans.…”

Section: Lipoprotein(a) and Remnant Lipoproteinsmentioning

confidence: 99%

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

2007

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Abstract-The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Local biological responses to these retained lipoproteins, including a chronic and maladaptive macrophageand T-cell-dominated inflammatory response, promote subsequent lesion development. The most effective therapy against atherothrombotic cardiovascular disease to date-low density lipoprotein-lowering drugs-is based on the principle that decreasing circulating apolipoprotein B lipoproteins decreases the probability that they will enter and be retained in the subendothelium. Ongoing improvements in this area include more aggressive lowering of low-density lipoprotein and other atherogenic lipoproteins in the plasma and initiation of low-density lipoprotein-lowering therapy at an earlier age in at-risk individuals. Potential future therapeutic approaches include attempts to block the interaction of apolipoprotein B lipoproteins with the specific subendothelial matrix molecules that mediate retention and to interfere with accessory molecules within the arterial wall that promote retention such as lipoprotein lipase, secretory sphingomyelinase, and secretory phospholipase A 2 . Although not the primary focus of this review, therapeutic strategies that target the proatherogenic responses to retained lipoproteins and that promote the removal of atherogenic components of retained lipoproteins also hold promise. The finding that certain human populations of individuals who maintain lifelong low plasma levels of apolipoprotein B lipoproteins have an Ϸ90% decreased risk of coronary artery disease gives hope that our further understanding of the pathogenesis of this leading killer could lead to its eradication.

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Proteoglycans Contribution to Association of Lp(a) and LDL With Smooth Muscle Cell Extracellular Matrix

Cited by 46 publications

References 49 publications

Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions

Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions

The epidermal growth factor–like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

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