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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that lipoprotein(a) [Lp(a)], an atherogenic lipoprotein that contains apolipoprotein(a), which shares partial structural homology to plasminogen, binds to a plasmin-modified fibrin surface, and we have postulated that this interaction may be atherogenic. Moderate elevations in blood homocysteine, a relatively common condition, predispose to premature atherosclerosis. The reasons for this are not established. We now report that homocysteine, at concentrations as low as 8 microM, significantly increases the affinity of Lp(a) for fibrin. Homocysteine induces a 20-fold increase in the affinity between Lp(a) and plasmin-treated fibrin and a 4-fold increase with unmodified fibrin. Lp(a) binding is inhibited by epsilon-aminocaproic acid, indicating lysine binding site specificity. Homocysteine does not enhance the binding of Lp(a) to other surface-bound proteins. Cysteine, glutathione, and N-acetylcysteine also increase the affinity between Lp(a) and fibrin. Homocysteine does not affect the binding of low density lipoprotein or plasminogen to fibrin, nor does it alter the gel-filtration elution pattern of Lp(a). Immunoblot analysis documents the fact that homocysteine partially reduces Lp(a). These results suggest that homocysteine alters the intact Lp(a) particle so as to increase the reactivity of the plasminogen-like apolipoprotein(a) portion of the molecule. The observation that sulfhydryl amino acids increase Lp(a) binding to fibrin suggests a biochemical relationship between sulfhydryl compound metabolism, thrombosis, and atherogenesis.
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PMID:Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. 143 9

New experimental evidence has shed light on a number of fundamental processes that contribute to atherosclerotic plaque formation. Recent data suggest that oxidized low-density lipoprotein (LDL) may be more avidly bound and taken up by macrophages, and thus more atherogenic, than unmodified LDL. A subclass of LDL, lipoprotein(a), is also of interest with respect to atherogenic potential, particularly since it has a plasminogen-like moiety as part of its structure. It may promote platelet aggregation and thrombus formation and thereby contribute to atherosclerotic plaque growth. Hypercholesterolemia, hypertension, and possibly other factors may induce changes in endothelial structure and function, which appear to be relatively early events associated with arterial injury. Smooth muscle cell proliferation and accumulation are hallmarks of arterial lesions induced by both hypertension and hypercholesterolemia, and several growth factors have been potentially implicated in these responses. Hypertension by itself causes arterial damage, but it does not appear to induce atherosclerosis when plasma lipid concentrations are low. In combination with hypercholesterolemia, however, it is a potent promoter of atherogenesis, and the mechanisms for this more-than-addictive effect are now the focus of considerable investigative attention.
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PMID:Pathophysiology of atherosclerosis. 144 96

Lipoprotein(a) (Lp[a]) is a low density lipoprotein particle that contains plasminogen-like apolipoprotein(a). Recent studies suggest an association of Lp(a) with atherosclerotic vascular disease. We have studied the accumulation of Lp(a) in atherosclerotic arteries of monkeys with diet-induced atherosclerosis. Immunohistochemistry with monospecific Lp(a) antisera revealed striking accumulations of Lp(a) in atherosclerotic coronary artery lesions. There was no Lp(a) in the normal, nonatherosclerotic arteries. Analysis of paired tissue and serum samples from 17 male hyperlipoproteinemic monkeys revealed a significant correlation between aortic wall Lp(a) and serum Lp(a) levels. The serum cholesterol level failed to correlate with either aortic Lp(a) or serum Lp(a). These results add further evidence for the potential role of Lp(a) in the pathogenesis of atherosclerosis.
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PMID:Lipoprotein(a) in diet-induced atherosclerosis in nonhuman primates. 182 15

Endothelial cells play a critical role in thromboregulation by controlling the assembly of fibrinolytic constituents on the membrane. The assembly system illustrated in FIGURE 6 is characterized by the binding of circulating glu-plasminogen to a membrane receptor (Pathway 1). A membrane-associated protease (possibly plasmin) converts the inactive zymogen into a catalytically more efficient zymogen lys-plasminogen (Pathway 2). T-PA binds to a specific receptor, retains its catalytic activity, and is protected from its natural inhibitor PAI-1. The membrane provides a favorable environment for plasmin generation (Pathway 3) at the vessel surface and contributes to the maintenance of a physiological nonthrombogenic state. The immobilization and surface activation of plasminogen provides an important mechanism for localizing proteolytic activity at the surface of other cells such as macrophages and tumor cells. Lp(a), a plasminogen-like lipoprotein, by competing at the endothelial surface for plasminogen binding down-regulates endothelial cell plasmin generation and may thus promote localized thrombogenesis that over a period of time contributes to progressive atherosclerosis.
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PMID:Endothelial cell fibrinolytic assembly. 190 39

Endothelial cells play a critical role in thromboregulation by virtue of a surface-connected fibrinolytic system. Cultured endothelial cells synthesize and secrete tissue-type plasminogen activator (t-PA) which can bind to at least two discrete sites on the cell surface. These binding sites preserve the catalytic activity of t-PA and protect it from its physiological inhibitor (PAI-1). N-terminal glutamic acid plasminogen (Glu-PLG), the main circulating fibrinolytic zymogen, also interacts specifically with the endothelial cell surface. Binding is associated with a 12-fold increase in catalytic efficiency of plasmin generation by t-PA which may reflect conversion of Glu-PLG to its plasmin-modified form, N-terminal lysine plasminogen (Lys-PLG). Lipoprotein(a) is an atherogenic lipoprotein particle which contains the plasminogen-like apolipoprotein(a) bound to low density lipoprotein. We report here that lipoprotein(a) interferes with endothelial cell fibrinolysis by inhibiting plasminogen binding and hence plasmin generation. In addition, we demonstrate lipoprotein(a) accumulation in atherosclerotic lesions. These findings may provide a link between impaired cell surface fibrinolysis and progressive atherosclerosis.
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PMID:Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. 252 66

Human lipoprotein(a) is a low density lipoprotein-like lipoprotein whose concentration in plasma is correlated with atherosclerosis. The characteristic protein component of lipoprotein(a) is apolipoprotein(a) (apo(a)) which is disulfide-linked to apolipoprotein B-100. Sequencing of rhesus monkey apo(a) cDNA suggests that this protein, like human apo(a), is highly similar to plasminogen. Sequence data suggests that a plasminogen-like protease activity and kringle 1-, 2-, 3-, and 5-like domains are unnecessary for apo(a) function, but a highly repeated kringle four-like domain is important. Liver is the major site of apo(a) RNA synthesis; reduced amounts of message were also found in testes and brain. Co-expression with apoB-100 and plasminogen in rhesus tissues is not mandatory.
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PMID:Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis. 292 43

Lipoprotein(a) is an LDL-like lipoprotein whose concentration in plasma is correlated with atherosclerosis. The characteristic protein component of lipoprotein(a) is apolipoprotein(a) which is disulphide-linked to apolipoprotein B-100. Sequencing of cloned human apolipoprotein(a) complementary DNA shows that it is very similar to human plasminogen. It contains a serine protease domain and two types of plasminogen-like kringle domains, one of which is present in 37 copies.
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PMID:cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. 367 Apr

Lipoprotein (a) is a major inherited risk factor for vascular diseases, including coronary atherosclerosis, restenosis, and stroke. The pathologic mechanisms are uncertain, but are likely to involve the unique plasminogen-like component of this lipoprotein, apolipoprotein (a). Studies suggest that apolipoprotein (a) can enhance lipid deposition in vessel walls, interfere with fibrinolysis, modulate smooth muscle cell activity, and induce endothelial dysfunction. This review discusses the key concepts relating to these mechanisms, with emphasis on recent studies.
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PMID:Vascular interactions of lipoprotein (a). 798 58

To elucidate the atherogenicity of lipoprotein(a) (Lp(a)), we examined its growth-stimulating activity in rat resident peritoneal macrophages. When macrophages were incubated with Lp(a), cell numbers were increased 1.5-fold as compared with control macrophages. Furthermore, apolipoprotein(a) (apo(a)), a plasminogen-like glycoprotein which is covalently attached to a low density lipoprotein-like particle (Lp(a)), also induced macrophage growth, while the growth-stimulating effect of Lp(a-) was negligible. These results suggest that apo(a) plays an active role in the mitogenic activity of Lp(a). Lp(a)-induced macrophage growth was inhibited by exogenously added active transforming growth factor-beta (TGF-beta) dose-dependently, and also by the addition of plasmin, which converts latent TGF-beta to an active form. Moreover, the amounts of endogenous active TGF-beta in the medium were significantly reduced by the incubation with Lp(a). It is evident from these results that Lp(a) induces macrophage growth by inhibiting TGF-beta activation. The capacity of Lp(a) to stimulate macrophage growth shown here could be novel atherogenic function of Lp(a).
Atherosclerosis 1996 Aug 23
PMID:Lipoprotein(a) induces cell growth in rat peritoneal macrophages through inhibition of transforming growth factor-beta activation. 883 23

Lipoprotein(a) contributes to the development of atherosclerosis through the binding of its plasminogen-like apolipoprotein(a) component to fibrin and other plasminogen substrates. Apolipoprotein(a) contains a major lysine binding site in one of its kringle domains. Destruction of this site by mutagenesis greatly reduces the binding of apolipoprotein(a) to lysine and fibrin. Transgenic mice expressing this mutant form of apolipoprotein(a) as well as mice expressing wild-type apolipoprotein(a) have been created in an inbred mouse strain. The wild-type apolipoprotein(a) transgenic mice have a fivefold increase in the development of lipid lesions, as well as a large increase in the focal deposition of apolipoprotein(a) in the aorta, compared with the lysine binding site mutant strain and to nontransgenic littermates. The results demonstrate the key role of this lysine binding site in the pathogenic activity of apolipoprotein(a) in a murine model system.
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PMID:Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice. 923 2


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