Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice.

Boonmark, Nataya W.; Lou, Xing Jian; Yang, Zhuoying; Schwartz, K.; Zhang, Junli; Rubin, Edward M.; Lawn, Richard M.

doi:10.1172/jci119565

Cited by 81 publications

(69 citation statements)

References 56 publications

(51 reference statements)

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“…The LBS of KIV 10 apo(a) consists of seven amino acids as follows by convention using the nomenclature of KV of PLG: Arg 35 . Because of the presence of several naming systems in the literature and differences in the number of amino acids in Ks between species, we provide a comparative summary of PLG KIV and KV, and apo(a) KIV 10 of various species in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To generate 8K-IV apo(a)/Lp(a) mice with defective KIV 10 LBS [8K-IV LBS Ϫ apo(a)/Lp(a) mice], the Asp 55 and Asp 57 residues in the KIV 10 LBS apo(a) cDNA construct were replaced by Ala 55 and Ala 57 residues, as previously described ( 35 ). The vector, pRK5 ha8Lysmuta, was digested with Bgl II, polished with Pfu DNA polymerase (Stratagene, La Jolla, CA), and cut with Eco RI.…”

Section: Generation Of 8k-iv Apo(a)/lp(a) Mice With Defective Kiv 10 Lbsmentioning

confidence: 99%

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Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Leibundgut

Scipione

Yin

et al. 2013

Journal of Lipid Research

187

146

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Section: Resultsmentioning

confidence: 99%

Section: Generation Of 8k-iv Apo(a)/lp(a) Mice With Defective Kiv 10 Lbsmentioning

confidence: 99%

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Leibundgut

Scipione

Yin

et al. 2013

Journal of Lipid Research

187

146

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“…59 Furthermore, it has been shown that modification of apo(a) lysinebinding sites reduces atherosclerosis in transgenic mice. 32 The acquired decrease in plasminogen and the elevated levels of Lp(a) observed in our patients may thus be considered a predisposing condition to thrombosis and atherosclerosis. Therefore, the plasma Lp(a)/plasminogen modifications doc- as a function of the apo(a) isoform/plasminogen concentration ratio.…”

Section: Discussionmentioning

confidence: 63%

“…18 The mechanism by which Lp(a) may favor the atherothrombotic process may be related to the lysine-binding properties of apo(a). 32,57 It has been proposed that Lp(a) may inhibit the binding of plasminogen to cells and fibrin by a competitive mechanism and, thereby, interfere with the fibrinolytic process. 28,29,31 Furthermore, we have previously shown that in subjects heterozygous for the apo(a) trait, the influence of the various apo(a) isoforms on fibrinolysis depends on their affinity for fibrin and on their concentrations relative to each other and to plasminogen.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the competitive binding of Lp(a) for lysine residues of fibrin and cell membrane proteins results in decreased plasmin formation and may favor the deposit of fibrin and lipids within the vascular wall. 32 Because a decreased plasminogen activation may be associated with thrombosis, 33,34 we thought it interesting to explore the interactions of Lp(a) with this enzyme system in nephrotic children. We hypothesized that the low levels of plasminogen and the high levels of Lp(a) induced by the nephrotic syndrome may favor binding of Lp(a) to fibrin and to human monocytes, thus inducing a decrease in fibrinolysis and pericellular proteolysis, which may contribute to the development of atherothrombosis.…”

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confidence: 99%

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Effect of Individual Plasma Lipoprotein(a) Variations In Vivo on Its Competition With Plasminogen for Fibrin and Cell Binding

Soulat

Loyau

Baudouin

et al. 2000

ATVB

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Abstract-Simultaneous natural changes in lipoprotein(a) [Lp(a)] and plasminogen occur in the nephrotic syndrome and offer a unique opportunity to investigate their effects on plasminogen activation under conditions fashioned in vivo. Plasminogen, Lp(a), and apolipoprotein(a) in plasma were characterized, and their competitive binding to carboxyterminal lysine residues of fibrin and cell membrane proteins was determined in nephrotic children during a flare-up of the disease (61 cases) and after 6 weeks (33 cases) and 6 months (42 cases) of remission. Low plasminogen concentrations (median 1.34 mol/L, range 0.39 to 1.96 mol/L) and high Lp(a) levels (median 0.27 g/L, range 0.07 to 2.57 g/L) were detected at flare-up. These changes were associated with an increased Lp(a) binding ratio onto fibrin (3.13Ϯ0.48) and cells (1.53Ϯ0.24) compared with binding ratios of control children (1.31Ϯ0.19 and 1.05Ϯ0.07, respectively) with normal plasminogen and low Lp(a) (median 0.071 g/L). After 6 weeks and 6 months of remission, the values for net decrease in Lp(a) binding to fibrin were 1.7Ϯ0.22 (after 6 weeks) and 1.88Ϯ0.38 (after 6 months) and were correlated with low Lp(a) concentrations (median 0.2 g/L, range 0.07 to 0.8 g/L; and median 0.12 g/L, range 0.07 to 1.34 g/L) and inversely associated with increased plasminogen levels (median 1.82 mol/L, range 1.4 to 2.1 mol/L; and median 1.58 mol/L, range 1.1 to 2.1 mol/L). These studies provide the first quantitative evidence that binding of Lp(a) to lysine residues of fibrin and cell surfaces is directly related to circulating levels of both plasminogen and Lp(a) and that these glycoproteins may interact as competitive ligands for these biological surfaces in vivo. This mechanism may be of relevance to the atherothrombotic role of Lp(a), particularly in nephrotic patients.

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Lipoprotein(a): New insights into mechanisms of atherogenesis and thrombosis

Deb

Caplice

2004

Clinical Cardiology

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Lipoprotein(a) (Lp[a]) continues to be a controversial molecule regarding its role in human vascular disease. Although the physiologic role of this molecule is still unclear, novel discoveries within the last few years have suggested numerous mechanisms whereby Lp(a) may contribute to atherosclerosis and its complications in human subjects. These effects may differentially occur in vascular tissue and circulating blood compartments. A complex interplay between tissue‐specific effects is probably more relevant to the pathogenicity of this molecule than one single effect alone. This review briefly describes the structure of Lp(a) in relation to its biochemical function, summarizing the current literature on various patho‐physiologic mechanisms of Lp(a)‐induced vascular disease and the role of cell and tissue‐specific effects in promoting atherogenesis and thrombosis.

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Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice.

Cited by 81 publications

References 56 publications

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Effect of Individual Plasma Lipoprotein(a) Variations In Vivo on Its Competition With Plasminogen for Fibrin and Cell Binding

Lipoprotein(a): New insights into mechanisms of atherogenesis and thrombosis

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