Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.

Rath, Matthias; Niendorf, Axel; Reblin, Tjark; Dietel, Manfred; Krebber, Hans-Joachim; Beisiegel, Ulrike

doi:10.1161/01.atv.9.5.579

Cited by 425 publications

(155 citation statements)

References 45 publications

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“…Lp(a) was observed mainly at the margins of the cholesterol crystal deposits. In the intima and subintima, Lp(a) was closer to the lumen, similar to what was formerly described for the aorta and coronary arteries, [63][64][65] and often colocalized with fibrin II deposits. That might interfere with the assembly of fibrinolytic proteins on the fibrin surfaces, thereby hampering fibrinolysis.…”

Section: Relationships Among Lipids Apolipoproteins and Thrombosissupporting

confidence: 85%

Noncollagenous Bone Matrix Proteins, Calcification, and Thrombosis in Carotid Artery Atherosclerosis

Bini

Mann

Kudryk

et al. 1999

ATVB

141

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Abstract-Advanced atherosclerosis is often associated with dystrophic calcification, which may contribute to plaque rupture and thrombosis. In this work, the localization and association of the noncollagenous bone matrix proteins osteonectin, osteopontin, and osteocalcin with calcification, lipoproteins, thrombus/hemorrhage (T/H), and matrix metalloproteinases (MMPs) in human carotid arteries from endarterectomy samples have been determined. According to the recent American Heart Association classification, 6 of the advanced lesions studied were type V (fibroatheroma) and 16 type VI (complicated 4 and ex vivo 5 detection of calcium deposits in coronary arteries, have shown that calcification is correlated with atherosclerotic plaque burden and that noninvasive detection of calcification may have predictive value in the development of subsequent coronary events. 5 The molecular determinants regulating extracellular matrix calcification have yet to be identified. Recent studies have shown that noncollagenous bone matrix proteins such as osteonectin, osteocalcin, and osteopontin are also found in atherosclerotic vessels and may regulate dystrophic calcification. For example, osteonectin (SPARC) has been identified in vessel wall cells 6 and platelets 7 and participates in the regulation of bone mineralization, 8 cell migration/proliferation, 9 and remodeling of extracellular matrix. 10 -12 Recently, it has been shown that osteonectin binds to plasminogen, 13 increases its activation and binding to collagen, 13 and induces the expression of type 1 plasminogen activator inhibitor in endothelial cells (ECs). 14 That suggests a role for osteonectin in both the degradation of extracellular matrix and the regulation of fibrinolysis. Moreover, osteonectin upregulates the expression of matrix metalloproteinases (MMPs) in cultured fibroblasts. 15 Previous studies have implicated MMPs in destabilization and rupture of atherosclerotic plaques, 16 -19 and we recently showed that both fibrinogen and cross-linked fibrin, proteins known to be associated with both early and complicated plaques, can be degraded by MMP-2,

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Section: Relationships Among Lipids Apolipoproteins and Thrombosissupporting

confidence: 85%

Noncollagenous Bone Matrix Proteins, Calcification, and Thrombosis in Carotid Artery Atherosclerosis

Bini

Mann

Kudryk

et al. 1999

ATVB

141

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“…12 Moreover, Lp(a) is more highly concentrated in the arterial wall than in plasma. Plasma-derived Lp(a) is known to penetrate human arteries 31 and the arteries of mice. 32 Therefore, a high serum Lp(a) concentration might affect blood vessel formation, such as collateral formation in ischemic disease.…”

Section: Discussionmentioning

confidence: 99%

Impairment of Collateral Formation in Lipoprotein(a) Transgenic Mice

et al. 2002

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Background-Although lipoprotein(a) (Lp[a]) is a risk factor for atherosclerosis, no study has documented the effects of Lp(a) on angiogenesis. In this study, we examined collateral formation in peripheral arterial disease (PAD) model in Lp(a) transgenic mice. In addition, we examined the feasibility of gene therapy by using an angiogenic growth factor, hepatocyte growth factor (HGF), to treat PAD in the presence of high Lp(a). Methods and Results-In Lp(a) transgenic mice, the degree of natural recovery of blood flow after operation was significantly lower than that in nontransgenic mice. Of importance, there was a significant negative correlation between serum Lp(a) concentration and the degree of natural recovery of blood flow (PϽ0.05). In addition, Lp(a) significantly stimulated the growth of vascular smooth muscle, accompanied by the phosphorylation of ERK. These data demonstrated the association of impairment of collateral formation with serum Lp(a) concentration. Thus, we examined the feasibility of therapeutic angiogenesis by using HGF, with the goal of progression to human gene therapy. In a large proportion of these patients, the anatomic extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. 2,3 One of the risk factors related to peripheral arterial disease is a high concentration of serum lipoprotein(a) (Lp[a]) because Lp(a) is also a risk factor for atherosclerosis, restenosis after angioplasty, ischemic heart disease, and cerebral stroke. 4 -9 Lp(a) consists of LDL with an additional protein component, apolipoprotein (a) (apo [a]), a homologue of plasminogen. 10 Lp(a) and apo(a) have been thought to enhance proliferation of human vascular smooth muscle cells (VSMCs). [11][12][13][14] On the other hand, Lp(a) has been postulated to bind to endothelial cells and macrophages and to extracellular components such as fibrin and inhibit cell-associated plasminogen activation. 15,16 Moreover, the inhibition of activation of transforming growth factor (TGF)-␤ by Lp(a) because of its strong homology to plasminogen has been reported. 11 Because TGF-␤ is also known to have proangiogenic properties, Lp(a) might inhibit angiogenesis from this aspect. In contrast, there is less evidence for the stimulation of Lp(a) on angiogenesis, although the proliferation of VSMCs might promote collateral formation in the case that endothelial cells would be stimulated by Lp(a). Nevertheless, no [17][18][19][20] Thus, a strategy for therapeutic angiogenesis with the use of angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. In addition to VEGF, we and others have reported the angiogenic property of hepatocyte growth factor (HGF) in a rabbit ischemia model. [21][22][23][24] Thus, it is preferable to stimulate angiogenesis by HGF, not only in a normal model but also in other high-risk conditions such as ...

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“…This novel observation may have biological relevance in that it might explain the results of the studies showing that the subendothelial matrix of the arterial wall retains Lp(a) preferentially over LDL (49 -51). In this context, it is important to point out that free apo(a) has been reported at the site of atheromatous lesions (52)(53)(54). This apo(a) may be either free standing or, based on the in vitro binding data, more likely associated with macromolecules of the extracellular matrix, namely fibrinogen (38,55), fibronectin (56,57), and potentially collagen.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein(a) Binds via Its C-terminal Domain to the Protein Core of the Proteoglycan Decorin

Klezovitch¹,

Edelstein²,

Zhu³

et al. 1998

Journal of Biological Chemistry

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Although it is known that lipoprotein(a) (Lp(a)) binds to proteoglycans, the mechanism for this binding has not been fully elucidated. In order to shed light on this subject, we examined the interactions of decorin, a proteoglycan with a well defined protein core and a single glycosaminoglycan (GAG) chain, with Lp(a) and derivatives, namely Lp(a) deprived of apo(a), or Lp(a؊), free apo(a), and the two main proteolytic fragments, F1 and F2. By circular dichroism criteria, the decorin preparations used had the same secondary structure as that previously reported for native decorin. Authentic low density lipoprotein from the same human donor was used as a control. In a solid phase system, Lp(a؊)and low density lipoprotein bound to decorin in a comparable manner. This binding required Ca 2؉ /Mg 2؉ ions, was lysine-mediated, and was markedly decreased in the presence of GAG-depleted decorin, suggesting the ionic nature of the interaction likely involving apoB100 and the GAG component of decorin. Free apo(a) also bound to decorin; however, the binding was neither cation-dependent nor lysine-mediated, unaffected by sialic acid depletion of apo(a), and markedly decreased when either reduced and alkylated apo(a) or reduced and alkylated decorin was used in the assay. Of note, the binding of apo(a) was unaffected when it was incubated with a spectrally native decorin that had been renatured from either 4 M guanidine hydrochloride by extensive dialysis or cooled from 65 to 25°C. On the other hand, the binding significantly increased when decorin was depleted of GAGs, which by themselves had no affinity for apo(a). The binding of apo(a) to the decorin protein core was also elicited by the C-terminal domain of apo(a), and it was favored by high NaCl concentrations, 1 to 2 M. No binding was exhibited by the N-terminal domain accounting for the lack of effect of apo(a) size polymorphism on the binding. In the case of whole Lp(a), the binding to immobilized decorin was mostly GAGdependent and ionic in nature. A minor contribution by apo(a) was detected when GAG-depleted decorin was used in the assay. Our results indicate that the binding of Lp(a) to decorin involves interactions both electrostatic (apoB100-GAG) and hydrophobic (apo(a)-decorin protein core), and that the binding of apo(a) requires decorin protein core to be in its native state.

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Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.

Cited by 425 publications

References 45 publications

Noncollagenous Bone Matrix Proteins, Calcification, and Thrombosis in Carotid Artery Atherosclerosis

Noncollagenous Bone Matrix Proteins, Calcification, and Thrombosis in Carotid Artery Atherosclerosis

Impairment of Collateral Formation in Lipoprotein(a) Transgenic Mice

Apolipoprotein(a) Binds via Its C-terminal Domain to the Protein Core of the Proteoglycan Decorin

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