Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Substantial experimental evidence now implicates lipoprotein (a) as an independent risk factor for premature cardiovascular disease. Both plasma Lp(a) levels and apo(a) phenotype are strong predictors of risk for ischaemic heart disease. The accumulation of apo(a) in vascular wall tissue and in atherosclerotic plaques and the potential inhibition of fibrinolysis by Lp(a) underlie the enhanced risk of premature cardiovascular disease associated with this cholesterol-rich particle. Recent studies of the capacity of purified Lp(a) isoforms to inhibit fibrinolysis in an in vitro system have revealed that small isoforms of Lp(a) (< or = 500 kDa) are efficient inhibitors of plasminogen activation and bind with high affinity to fibrin. Conversely, large isoforms exert little or no inhibitory effect in this system (> 500 kDa). These data suggest that the potential, high affinity interaction of Lp(a) particles containing small isoforms with fibrin introduces a new, third dimension to the atherothrombotic risk associated with these cholesterol-rich particles.
Atherosclerosis 1994 Oct
PMID:Lipoprotein (a): implication in atherothrombosis. 785 88

Plasminogen activator inhibitor-1 (PAI-1), specific inhibitor of plasminogen activators (PA), plays an important role in the regulation of fibrinolysis. Increased levels of PAI-1 have been associated with vascular disease such as thrombosis and atherosclerosis. In the present study the expression of PAI-1 mRNA in human healthy, atherosclerotic and thrombotic blood vessel walls was quantified by RNA-RNA hybridization in solution and localized by in situ hybridization. The mean expression of PAI-1 mRNA was significantly higher in healthy arteries (0.86 pg/microgram total RNA) than in healthy veins (0.29 pg/microgram total RNA), p < 0.01. The mean PAI-1 mRNA expression in thrombotic arteries (1.72 pg/micrograms total RNA) was significantly higher than that in healthy arteries, p < 0.05, and the mean PAI-1 mRNA expression in thrombotic veins (1.29 pg/micrograms total RNA) was significantly higher than that in healthy veins, p < 0.01. By in situ hybridization PAI-1 mRNA was detected in the intima, media and adventitia of healthy arteries and healthy veins. In atherosclerotic arteries PAI-1 mRNA was detected in the atherosclerotic plaque and in the medial and adventitial layers below the plaque. An increased expression of PAI-1 mRNA was found in the intimal layer of a thrombotic vein. The increased expression of PAI-1 mRNA in thrombotic arteries and veins indicates a role for PAI-1 in thrombogenesis.
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PMID:Expression of plasminogen activator inhibitor-1 mRNA in healthy, atherosclerotic and thrombotic human arteries and veins. 790 96

Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).
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PMID:Lipoprotein(a) in health and disease. 791 1

The relationship of ischaemic heart disease (IHD) to seasonal and latitude variation has prompted speculation that exposure to the ultraviolet component of solar radiation may reduce IHD risk. This hypothesis was partially tested by exposing 14 post-myocardial infarction patients to a 6 week course of artificial whole-body ultraviolet radiation (UVR). Serum lipoprotein and plasma coagulation factor concentrations were measured before and after the course of UVR. Results were compared with similar measurements from a placebo-controlled group of 13 post-myocardial patients. Despite a more than two-fold rise in mean serum 25-OHD, serum lipoprotein and plasma fibrinogen, antithrombin III and plasminogen concentrations did not change significantly in the UVR group. Significant but minor change in prothrombin time and thrombin time in the placebo group appear unlikely to be of biological significance. Seasonal and latitude variation in these IHD risk factors appear unrelated to corresponding variation in solar UVR exposure.
Atherosclerosis 1994 May
PMID:Artificial ultraviolet whole-body radiation does not modify serum lipoprotein, plasma fibrinogen, plasminogen or antithrombin III concentrations in post-myocardial infarction patients. 794 60

Elevated levels of lipoprotein(a), which consists of apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein-like moiety, is an independent risk factor for the development of atherosclerosis. We show that a recombinant form of apo(a) [r-apo(a)] binds strongly to fibronectin and fibrinogen, weakly to laminin, and not at all to von Willebrand factor, vitronectin, or collagen type IV. In contrast to the binding of plasminogen to fibronectin, r-apo(a) binding does not appear to be mediated by lysine-dependent interactions, based on the inability of epsilon-aminocaproic acid concentrations up to 0.2 mol/L to significantly decrease r-apo(a) binding to fibronectin. Plasminogen competed weakly for the binding of r-apo(a) to fibronectin, whereas r-apo(a) completely abolished plasminogen binding. The 29- and 38-kd heparin-binding thermolysin fragments of fibronectin, previously identified as the lipoprotein(a) binding domains, were digested with trypsin, and a peptide that retained the ability to bind r-apo(a) was isolated; the sequence of the peptide (AVTTIPAPTDLK) corresponds to the amino terminus of the 29- and 38-kd domains. A synthetic peptide with this sequence was able to compete effectively with fibronectin for r-apo(a) binding.
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PMID:Binding of recombinant apolipoprotein(a) to extracellular matrix proteins. 794 5

Lp(a) is an LDL-like lipoprotein that is a major inherited risk factor for atherosclerosis. It is distinguished from Lp(a) by the addition of apolipoprotein(a). The gene structure of apolipoprotein(a) is homologous to plasminogen, and competition with plasminogen activity may account for some of the pathophysiology associated with Lp(a). Six highly related genes have now been identified, and at least four are found in close proximity in overlapping genomic clones. Studies have begun on the regulation of apolipoprotein (a) gene expression, and the human apolipoprotein(a) gene has been inserted into transgenic mice, where it leads to the development of arterial lesions.
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PMID:Studies on the structure and function of the apolipoprotein(a) gene. 798 75

Sixteen patients with lower limb atherosclerosis (LLAS) stage II-III received autotransfusions of blood irradiated by ultraviolet light. Vascular wall antithrombogenic properties assessed before the treatment in the patients and controls were found deteriorated in LLAS subjects. The cuff test did not affect the antithrombogenic characteristics. The course of autotransfusions produced a clinical improvement and strengthening of the antithrombogenic properties. The cuff test demonstrated a significant decline in platelet aggregation in response to ADP, thrombin, collagen, ristomycin, arachidonic acid; of platelet factor 4, thromboxane B2, beta-thromboglobulin. Concentrations of antithrombin III, plasminogen, prostacyclin rose. The autotransfusions were made on "Izolda" device MD-73 (1 ml of blood per 1 kg b. mass). Irradiation dose 750 J/m2, wave length 254 nm. Platelet aggregation was studied according to Born technique in O'Brien modification. Thromboxane B2, 6-keto-PGF1 alpha, beta-thromboglobulin and TF 4 were measured by radioimmunoassay, antithrombin III and plasminogen by chromogenic substrates.
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PMID:[The antithrombogenic properties of the vascular wall and platelet aggregation in patients with atherosclerosis of the arteries of the lower extremities following a course of treatment with UV-irradiated autologous blood transfusion]. 802 Jul 15

A HIGH concentration of serum lipoprotein(a) is a risk factor for atherosclerosis. Lipoprotein(a) consists of low-density lipoprotein with the additional protein component, apolipoprotein(a), a homologue of plasminogen. Lipoprotein(a) and apolipoprotein(a) enhance proliferation of human vascular smooth muscle cells (hVSMCs) in culture by inhibiting activation of plasminogen to plasmin, thus blocking the proteolytic activation of transforming growth factor-beta (TGF-beta), an autocrine inhibitor of hVSMC proliferation. The hypothesis that this pathway is a key step in atherogenesis is tested on transgenic mice expressing the human apolipoprotein(a) gene. We show here that the activation of TGF-beta is inhibited in the aortic wall and serum of mice expressing apolipoprotein(a), as a consequence of apolipoprotein(a) inhibition of plasminogen activation. These effects are closely correlated with VSMC activation.
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PMID:Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice. 804 65

Elevated levels of lipoprotein(a) (Lp(a)) have been strongly correlated with the development of atherosclerosis in human populations. Lp(a) is distinguishable from low density lipoprotein by the presence of the unique protein component apolipoprotein(a) (apo(a)), which contains repeated domains that closely resemble that of plasminogen kringle IV. Using human embryonic kidney cells, we have expressed a recombinant form of apo(a) (r-apo(a)) containing 17 kringle IV-like domains. We have utilized this recombinant expression system to study the assembly of Lp(a) particles. We have demonstrated that Lp(a) particles containing r-apo(a) can be assembled extracellularly in plasma by covalent linkage to low density lipoprotein. Using site-directed mutagenesis, we have demonstrated that a cysteine residue present at position 4057 of the apo(a) protein (i.e., in the penultimate kringle IV repeat) mediates this covalent linkage. Using polymerase chain reaction amplification of liver apo(a) complementary DNA, we have demonstrated the presence of a polymorphism in apo(a) kringle IV type 10, which results in the substitution of a threonine for a methionine. Preliminary studies indicate that the presence of a threonine at this position may enhance the interaction of Lp(a) with lysine-Sepharose.
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PMID:Analysis of structure--function relationships in human apolipoprotein(a). 806 77

Lipoprotein Lp(a) is a pluri-molecular complex rich in cholesterol and composed of an LDL (low-density lipoprotein) particle to which is attached a large glycoprotein, apolipoprotein(a) (apo(a)). Numerous epidemiological studies have established a strong correlation between plasma levels of Lp(a) and the premature development of atheromatous vascular disease in man, an association which has subsequently been confirmed by the detection of Lp(a) in human atherosclerotic plaques. Furthermore, a marked structural resemblance has been demonstrated between apo(a) and plasminogen, a key protein of the fibrinolytic system and responsible for dissolution of blood clots. This discovery has provided evidence, for the first time, that Lp(a) might constitute an important link between atherosclerosis and thrombosis. Intense research effort is now underway to provide further understanding of (I) the structural organisation of the Lp(a) particle; (II) the molecular genetics of apo(a); (III) the processes involved in the synthesis, assembly intravascular metabolism and degradation of Lp(a) and apo(a); (IV) the nature of the interactions of Lp(a) and apo(a) with cellular and non-cellular components of the arterial wall; (V) the role of Lp(a) in fibrinolysis, and (VI) the relationship between Lp(a) and certain metabolic disorders such as familial hypercholesterolemia. These fascinating questions will be examined in the light of studies of different models of transgenic mce expressing human apo(a) alone, or both apo(a) and apo B100. In man, CETP assures the transfer of cholesteryl ester from high-density lipoproteins (HDL) to lipoproteins containing apo-B, and notably VLDL, IDL and LDL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Lipoprotein Lp(a) and CETP (cholesterol ester transfer protein): contribution of transgenic mice]. 807 82


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