Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries

Niendorf, Axel; Rath, Matthias; Wolf, Katrin; Peters, Susanne; Arps, H; Beisiegel, Ulrike; Dietel, Manfred

doi:10.1007/bf02190527

Cited by 85 publications

(22 citation statements)

References 27 publications

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“…In agreement with a previous report (38), C 6 -1-palmitoyl-2-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]hexanoyl-sn-glycero-3-phosphocholine was found to be a substrate of the Lp(a) associated activity. As expected, the Lp(a) associated activity failed to cleave the ester bond of 1-palmitoyl-sn-2-glycero- [5,6,8,9,11,12,14, H] -arachidonyl-3-phosphocholine, indicating a preference for substrates with short acyl chains as reported for the isolated protein (20) (data not shown). Hence, the hydrolytic activity of Lp(a) displayed all characteristics known for the LDL-associated enzyme as well as for the purified PAF acetylhydrolase, indicating that this enzyme is the sole source of the Lp(a)-associated PAF hydrolytic activity.…”

Section: Inhibition Of Lp(a)-associated Paf Acetylhydrolase Activity-supporting

confidence: 80%

“…Apo(a) is linked to apoB, the main protein component of LDL, by a single disulfide bond (3,4) and exhibits a homology to plasminogen (5). In clinical studies, elevated Lp(a) plasma concentrations have been shown to correlate with the incidence of stroke and coronary heart disease (6 -8), and an accumulation in atherosclerotic lesions has been demonstrated (9), features that provide evidence for elevated Lp(a) levels as a substantial risk factor. Moreover, an overexpression of apo(a) promotes the development of lesions in transgenic animals (10).…”

Section: Lp(a)mentioning

confidence: 99%

“…1-Palmitoyl-sn-2-glycero- [5,6,8,9,11,12,14, H]-arachidonyl-3-phospho choline (45 mBq/mM) was prepared as described (27). BCA reagent with albumin as standard was obtained from Pierce Chemical Co. Econopac ® columns packed with Bio-Gel P-6DGel and disposable chromatography columns (Bio-Spin ® ) were from Bio-Rad (Mü nchen, Germany).…”

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confidence: 99%

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Enhanced Association of Platelet-activating Factor Acetylhydrolase with Lipoprotein (a) in Comparison with Low Density Lipoprotein

Blencowe

Hermetter

Kostner

et al. 1995

Journal of Biological Chemistry

100

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Paired samples of human Lipoprotein (a) (Lp(a)) and low density lipoprotein (LDL) were assayed for their platelet-activating factor (PAF) acetylhydrolase activity. Lp(a) displayed markedly enhanced PAF acetylhydrolase activity (approximately 7-fold based on equal particle concentrations) in comparison to LDL isolated from the same individual. Lp(a)-associated acetylhydrolase exhibited properties observed for LDL-associated acetylhydrolase as well as for the purified enzyme; significant inhibition was obtained by treatment with diisopropylfluorophosphate (1 mM, 90%) and phenylmethanesulfonyl fluoride (5 mM, 50%). Furthermore, the hydrolytic activity of both lipoproteins was abolished with paraoxon (6 mM, IC 50 0.9 mM) and with the fluorescent and active site-directed probe 4-hexyl-(6-O-butyl-(4-pyrenyl))-benzoic estersulfonyl fluoride (2) (K I(inact) ‫؍‬ 525 M), a novel irreversible inhibitor of PAF acetylhydrolase. Treatment with 2 and subsequent quantitation of protein-bound fluorescence suggests an increased concentration of enzyme associated to Lp(a) rather than alterations of kinetic constants due to the additional apolipoprotein apolipoprotein (a). Exposure of Lp(a) to Cu 2؉ (20 M, 37°C) was followed by a concomitant decrease of hydrolytic activity. A reduction of the basal activity by 91% was found after 15 h. Whereas immunoprecipitation with anti-apoB antiserum could remove enzymatic activity of Lp(a) regardless of a reductive treatment with dithiothreitol, precipitation with anti-apolipoprotein (a)-antibodies was accompanied by a minor reduction (approximately 30%) of the PAF-hydrolyzing ability. These results suggest that PAF acetylhydrolase exhibits an enhanced association with Lp(a) due to an increased affinity to Lp(a) apolipoprotein B. Lp(a)1 is a lipoprotein from human plasma differing from low density lipoprotein by apo(a) an additional unique glycoprotein (Ref. 1; for review see Ref.2). Apo(a) is linked to apoB, the main protein component of LDL, by a single disulfide bond (3, 4) and exhibits a homology to plasminogen (5). In clinical studies, elevated Lp(a) plasma concentrations have been shown to correlate with the incidence of stroke and coronary heart disease (6 -8), and an accumulation in atherosclerotic lesions has been demonstrated (9), features that provide evidence for elevated Lp(a) levels as a substantial risk factor. Moreover, an overexpression of apo(a) promotes the development of lesions in transgenic animals (10).

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Section: Inhibition Of Lp(a)-associated Paf Acetylhydrolase Activity-supporting

confidence: 80%

Section: Lp(a)mentioning

confidence: 99%

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Enhanced Association of Platelet-activating Factor Acetylhydrolase with Lipoprotein (a) in Comparison with Low Density Lipoprotein

Blencowe

Hermetter

Kostner

et al. 1995

Journal of Biological Chemistry

100

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“…Several groups of investigators have postulated that the ability of Lp(a) to compete for plasminogen binding sites on cells is important in certain potentially atherogenic processes, such as decreased fibronolysis (9 -11) and increased smooth muscle cell proliferation (12). Another possible clue to the potential atherogenicity of Lp(a) comes from the observation that Lp(a) and apo(a) are often physically in contact with cholesterol-loaded macrophages (foam cells) (13), which are prominent components of atherosclerotic lesions (14 -16). In previous work, we have demonstrated that mouse peritoneal and human monocyte-derived macrophages have a receptor activity that can bind, internalize, and lysosomally degrade Lp(a) (17,18).…”

Section: Lp(a)mentioning

confidence: 99%

The Binding Activity of the Macrophage Lipoprotein(a)/Apolipoprotein(a) Receptor Is Induced by Cholesterol via a Post-translational Mechanism and Recognizes Distinct Kringle Domains on Apolipoprotein(a)

Keesler

Gabel

Devlin

et al. 1996

Journal of Biological Chemistry

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Elevated plasma levels of lipoprotein(a) (Lp(a)) can be a risk factor for atherosclerosis, and the interaction of Lp(a) with cholesterol-loaded macrophages (foam cells) in atheromata may be important in Lp(a)-induced atherogenesis. We have previously shown that when cultured macrophages are loaded with cholesterol, they acquire the ability to internalize and lysosomally degrade Lp(a) via interaction between a novel cell-surface receptor activity and the apolipoprotein(a) (apo(a)) moiety of Lp(a). Herein we explore the cell-surface binding of recombinant apo(a) (r-apo(a)) by foam cells. Whereas the induction of degradation of r-apo(a) by cholesterol loading of macrophages depended on new protein synthesis, the induction of binding of r-apo(a) did not. Furthermore, J774 macrophages bound r-apo(a) in a cholesterol-regulatable and specific manner but degraded r-apo(a) poorly. Thus, the binding and internalization/ degradation functions of the receptor activity are distinct. To explore which domains on r-apo(a) interact with the foam cell receptor, we conducted a series of competitive and direct binding and degradation experiments using 12 r-apo(a) constructs that differed in their content of specific kringle subtypes. These data, as well as complementary data with anti-apo(a) monoclonal antibodies, indicated that the region centered around kringle type IV, subtypes 6-7 (KIV 6 -7 ) is important in receptor binding. Remarkably, a cholesterol-induced receptor activity with similar structural specificity was also found on Chinese hamster ovary cells. In conclusion, the foam cell Lp(a)/apo(a) receptor consists of a cholesterol-regulatable binding activity and a shortlived component necessary for internalization or lysosomal degradation; the binding activity interacts with a distinct region of apo(a) that is different from that involved in competition for plasminogen binding. Lp(a)1 is an LDL-like lipoprotein in which the apoB-100 moiety of LDL is covalently attached to a glycoprotein called apo(a) (1, 2). Apo(a) consists of multiple domains called kringles, which are regions of protein folds each stabilized by three disulfide bonds (3). Apo(a) shares 80% homology with another kringle-containing protein, plasminogen (3). Although the physiological role of Lp(a) is not known, elevated levels of this lipoprotein in certain human populations are often associated with increased risk for atherosclerotic coronary artery disease and stroke (4). Furthermore, Lp(a) transgenic mice (5, 6) and, in one report ( (7); cf. Ref. 8), apo(a) transgenic mice have been found to have accelerated atherosclerosis.The mechanism of Lp(a)-induced atherosclerosis is not known. Several groups of investigators have postulated that the ability of Lp(a) to compete for plasminogen binding sites on cells is important in certain potentially atherogenic processes, such as decreased fibronolysis (9 -11) and increased smooth muscle cell proliferation (12). Another possible clue to the potential atherogenicity of Lp(a) comes from the observation that Lp(a) an...

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“…In fact, apo(a) has been detected in nonlesion areas of arterial wall from children (15). Lp(a) in the arterial wall would strengthen the arteries, but atherosclerosis would occur, as described later, if this function were to operate to too great an extent.…”

mentioning

confidence: 84%

Hypothesis: lipoprotein(a) is a surrogate for ascorbate.

Rath

Pauling

1990

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

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The concept that lipoprotein (a) [Lp(a)] is a surrogate for ascorbate is suggested by the fact that this lipoprotein is found generally in the blood of primates and the guinea pig, which have lost the ability to synthesize ascorbate, but only rarely in the blood of other animals. Properties of Lp(a) that are shared with ascorbate, in accordance with this hypothesis, are the acceleration of wopnd healing and other cell-repair mechanisms, the strengthening of the extracellular matrix (e.g., in blood vessels), and the prevention of lipid peroxidation. High plasma Lp(a) is associated with coronary heart disease and other forms ofatherosclerosis in humans, and the incidence of cardiovascular disease is decreased by elevated ascorbate. Similar observations have been made in cancer and diabetes. We have formulated the hypothesis that Lp(a) is a surrogate for ascorbate in humans and other species and have marshaled the evidence bearing on this hypothesis.Lipoproteins consist of particles, each of which is a globule of lipid molecules surrounded by an apoprotein shell. Lipoprotein(a) [Lp(a)] was discovered by Blumberg et al. (1) and by Berg (2). It shares with low density lipoprotein (LDL) its lipid and apoprotein composition-mainly apoprotein B-100 (apo B), consisting of a polypeptide chain of 4536 amino acid residues. The unique feature of Lp(a) is an additional glycoprotein, designated apoprotein(a) [apo(a)], which is linked to apo B by disulfide groups. The cDNA sequence of apo(a) (3) shows a striking homology to plasminogen, with multiple repeats of kringle 4, one kringle 5, and a protease domain. The isoforms of apo(a) vary in the range of 300 to 800 kDa and differ mainly in their genetically determined number of kringle 4 structures (3); apo(a) has no plasmin-like protease activity (4), but a serine protease activity has been demonstrated recently (5). Like plasminogen, Lp(a) has been shown to bind to lysine-Sepharose, immobilized fibrin and fibrinogen (6), and the plasminogen receptor on endothelial cells (7)(8)(9). This binding is inhibited by E-aminocaproic acid, certain other amines, and plasminogen.

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Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries

Cited by 85 publications

References 27 publications

Enhanced Association of Platelet-activating Factor Acetylhydrolase with Lipoprotein (a) in Comparison with Low Density Lipoprotein

Enhanced Association of Platelet-activating Factor Acetylhydrolase with Lipoprotein (a) in Comparison with Low Density Lipoprotein

The Binding Activity of the Macrophage Lipoprotein(a)/Apolipoprotein(a) Receptor Is Induced by Cholesterol via a Post-translational Mechanism and Recognizes Distinct Kringle Domains on Apolipoprotein(a)

Hypothesis: lipoprotein(a) is a surrogate for ascorbate.

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