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)

Lp(a) represents a genetically transmitted class of plasma LDL having apo B-100 linked by a disulfide bridge to a glycoprotein, apo(a). Lp(a) is heterogeneous in size and density. Apo(a) is also heterogeneous in size (molecular weight between approximately 300,000 and 700,000) due probably to the polymorphism of both polypeptide and carbohydrate chains. Recent studies have shown that apo(a) has a striking amino acid sequence homology with plasminogen, a serine protease zymogen that following activation to plasmin enters the fibrinolytic system. Apo(a) is severalfold larger than plasminogen (molecular weight approximately 90,000) and also differs from it because it fails to be activated to plasmin. This is due to the fact that arginine is replaced by serine at the site of cleavage by streptokinase, urokinase, or tissue plasminogen activator. A single gene locus appears to control the Lp(a) polymorphism as well as the concentration of the Lp(a) phenotypes in the plasma. Patients with high plasma levels of Lp(a) have been shown to have an increased incidence of cardiovascular disease but a causal relationship has not been firmly established. The information that is being rapidly acquired on the structure of Lp(a) should facilitate the understanding of the molecular basis of the polymorphism of this genetic variant and of the role that the various Lp(a) phenotypes play in atherosclerosis and thrombosis. The potential physiologic role of Lp(a) remains open to inquiry.
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PMID:Lipoprotein(a): a genetically determined lipoprotein containing a glycoprotein of the plasminogen family. 297 66

Apolipoprotein(a) [apo(a)], the glycoprotein associated with the lipoprotein(a) [Lp(a)] subfraction of plasma lipoproteins, has been shown to exhibit heritable molecular weight isoforms ranging from 400-700 kDa. Increased serum concentrations of Lp(a) correlate positively with the risk of atherosclerosis. Variations in Lp(a) plasma levels among individuals are inherited as a codominant quantitative trait. As part of an effect to define the basis of these variations and further clarify the expression of the protein, we have determined the chromosomal location of the human apo(a) gene. Blot hybridization analysis of DNA from a panel of mouse-human somatic cell hybrids with an apo(a) cDNA probe revealed a complex pattern of bands, all of which segregated with chromosome 6. In situ hybridization yielded a single peak of grain density located on chromosome 6q26-27. Apo(a) cDNA sequences exhibit striking homology to those of the plasma protease plasminogen, and, therefore, we have reexamined the chromosome assignment of the plasminogen gene. We conclude that both the apo(a) and plasminogen genes reside on human chromosome 6q22-27, consistent with a gene duplication mechanism for their evolutionary origin. The results are of significance for the genetic control of apo(a) expression and genetic influences predisposing to atherosclerosis.
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PMID:The apolipoprotein(a) gene resides on human chromosome 6q26-27, in close proximity to the homologous gene for plasminogen. 341 Apr 59

Apolipoprotein(a) [apo(a)] is a glycoprotein with Mr approximately equal to 280,000 that is disulfide linked to apolipoprotein B in lipoprotein(a) particles. Elevated plasma levels of lipoprotein(a) are correlated with atherosclerosis. Partial amino acid sequence of apo(a) shows that it has striking homology to plasminogen. Plasminogen is a plasma serine protease zymogen that consists of five homologous and tandemly repeated domains called kringles and a trypsin-like protease domain. The amino-terminal sequence obtained for apo(a) is homologous to the beginning of kringle 4 but not the amino terminus of plasminogen. Apo(a) was subjected to limited proteolysis by trypsin or V8 protease, and fragments generated were isolated and sequenced. Sequences obtained from several of these fragments are highly (77-100%) homologous to plasminogen residues 391-421, which reside within kringle 4. Analysis of these internal apo(a) sequences revealed that apo(a) may contain at least two kringle 4-like domains. A sequence obtained from another tryptic fragment also shows homology to the end of kringle 4 and the beginning of kringle 5. Sequence data obtained from two tryptic fragments show homology with the protease domain of plasminogen. One of these sequences is homologous to the sequences surrounding the activation site of plasminogen. Plasminogen is activated by the cleavage of a specific arginine residue by urokinase and tissue plasminogen activator; however, the corresponding site in apo(a) is a serine that would not be cleaved by tissue plasminogen activator or urokinase. Using a plasmin-specific assay, no proteolytic activity could be demonstrated for lipoprotein(a) particles. These results suggest that apo(a) contains kringle-like domains and an inactive protease domain.
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PMID:Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. 347 6

We have previously studied cardiovascular risk markers apolipoprotein (a) (apo(a)) and plasma fibrinogen in 146 control, 60 haemodialysis (HD), 53 continuous ambulatory peritoneal dialysis (CAPD) and 66 renal transplant subjects. Fibrinogen concentration was higher in all 3 renal replacement groups compared to controls. Apo(a) was higher in the CAPD group only. We have now restudied those dialysis patients (24 HD, 16 CAPD) who have since undergone transplantation. Fibrinogen concentration remained elevated in CAPD patients (mean (SE) 3.9 (0.17) vs. 3.77 (0.20) grams/l) and increased in HD patients (2.88 (0.16) vs. 3.72 (0.13) grams/l, P < 0.0001). Apo(a) fell in both groups (CAPD, geometric mean 287 vs. 151 U/l, P = 0.008; HD, 230 vs. 179 U/l, P = 0.013). Fibrinogen concentration was higher in the recent group compared to the original group (3.74 (0.11) vs. 3.19 (0.12) grams/l, P = 0.001). None of the 66 original patients received cyclosporin (cyA) compared to 35 of the 40 in the present study. In this recent group, patients maintained on prednisolone and azathioprine alone had significantly lower fibrinogen levels than those receiving cyA. Furthermore, the fall in apo(a) was smaller (31% vs. 74%) and the increase in apolipoprotein B (apo B) greater (0.55 (0.15) vs. 0.18 (0.05) grams/l, P = 0.014) in cyA-treated patients. CyA may have an adverse effect on cardiovascular risk profile in renal transplant recipients.
Atherosclerosis 1995 Aug
PMID:Effect of immunosuppressive drug regime on cardiovascular risk profile following kidney transplantation. 757 79

The lipoprotein Lp(a), a major inherited risk factor for atherosclerosis, consists of a low density lipoprotein-like particle containing apolipoprotein B-100 plus the distinguishing component apolipoprotein(a) (apo(a)). Human apo(a) contains highly repeated domains related to plasminogen kringle four plus single kringle five and protease-like domains. Apo(a) is virtually confined to primates, and the gene may have arisen during primate evolution. One exception is the occurrence of an Lp(a)-like particle in the hedgehog. Cloning of the hedgehog apo(a)-like gene shows that it is distinctive in form and evolutionary history from human apo(a), but that it has acquired several common features. It appears that the primate and hedgehog apo(a) genes evolved independently by duplication and modification of different domains of the plasminogen gene, providing a novel type of "convergent" molecular evolution.
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PMID:The recurring evolution of lipoprotein(a). Insights from cloning of hedgehog apolipoprotein(a). 759 97

Lipoprotein (a) (Lp(a)) levels are genetically determined and levels higher than 25 mg/dl are associated with increased prevalence of coronary artery disease (CAD). We studied gender differences in 76 men and 20 women undergoing coronary artery bypass graft surgery (CABG) for a potential association between Lp(a) levels both in serum and the aortic wall (Apo(a)) and the severity of CAD determined by an atherosclerosis score (CS) using quantitative coronary angiography (QCA). Serum Lp(a) and tissue Apo(a) do not correlate with the severity of CAD as assessed from QCA (r = 0.09 and r = 0.14, resp.). 60% of women but only 39% of men had serum Lp(a) levels higher than 25 mg/dl. Women were 8 years older (65 +/- 8 vs. 57 +/- 8 years, p < 0.001) and had 1.5 times higher mean serum Lp(a) and 1.75 times higher mean tissue Apo(a) levels (47 +/- 41 vs. 32 +/- 40 mg/dl and 33 +/- 34 vs. 19 +/- 24 micrograms/g WW, p < 0.05) than men with identical CS (35 +/- 8 vs. 33 +/- 8, p = NS). The serum levels of cholesterol, triglycerides, and high-density lipoprotein were similar in the two groups. There is no association between Lp(a) and Apo(a) and the severity of coronary atherosclerosis in men and women undergoing coronary artery bypass surgery.
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PMID:[Association of lipoprotein (a) with the extent of coronary atherosclerosis in surgically revascularized men and women]. 771 22

High plasma concentrations of apolipoprotein (a) (apo(a)) have been implicated as a major independent risk factor for atherosclerosis in humans. Apo(a) is a large, evolutionarily new gene (present primarily in primates) for which considerable controversy exists concerning the factors that regulate its expression. To investigate the in vivo regulation of apo(a), we have created several lines of YAC transgenic mice containing a 110-kb human apo(a) gene surrounded by greater than 60 kb of 5' and 3' flanking DNA. Studies in humans have suggested that acute-phase inducers increase and sex steroids decrease apo(a) concentrations, but these results are controversial. Analysis of the YAC transgenic mice conclusively supports the hypothesized role of sex steroids and refutes the suggested role of acute-phase inducers in regulating the apo(a) gene.
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PMID:The apolipoprotein(a) gene is regulated by sex hormones and acute-phase inducers in YAC transgenic mice. 779 50

The association between apolipoprotein(a) [apo(a)], fibrinogen, fibrinopeptide A (FPA) and carotid intima-media thickness (IMT) was analyzed in Eastern Finnish men aged 50 to 60 years. Apo(a) correlated directly with carotid bifurcation (r = 0.26, p = 0.001), but not with common carotid IMT. Men in the lowest quartile of apo(a) had thinner (p = 0.013) IMT in bifurcation [1.59 mm (95% CI 1.49; 1.68)] compared to the men in the highest [1.91 mm (95% CI 1.73; 2.09)] apo(a) quartile. The difference remained (p = 0.038) after adjusting for confounders. Plasma fibrinogen was not related to carotid IMT, whereas FPA correlated with common carotid (r = 0.21, p = 0.016) and carotid bifurcation (r = 0.21, p = 0.018) IMT. These associations abolished after adjusting for the confounders. The data suggest that apo(a) associate with carotid atherosclerosis independent of other risk factors for ischemic cardiovascular diseases.
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PMID:Apolipoprotein(a), fibrinopeptide A and carotid atherosclerosis in middle-aged men. 858 28

High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. In the general population, Lp(a) levels are primarily determined by allelic variation at the apolipoprotein(a) [apo(a)] gene locus. Apo(a) isoforms of various sizes are associated with different Lp(a) concentrations. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by the size variation at the apo(a) gene locus. To further investigate the origin of the elevated Lp(a) plasma concentrations, we examined Lp(a) concentrations and apo(a) phenotypes in 154 ESRD patients undergoing renal transplantation. In a prospective longitudinal study we observed a rapid normalization of Lp(a) levels from an average concentration of 25.9 +/- 28.7 mg/dL before to 17.9 +/- 25.5 mg/dL 3 weeks after renal transplantation (P < .0001). Only patients with high-molecular-weight phenotypes had a significant decrease in Lp(a) plasma concentrations. This study demonstrates the nongenetic origin of elevated Lp(a) concentrations in ESRD patients, which is obviously caused by the disease. It further confirms a phenotype-associated elevation of Lp(a) concentrations in ESRD.
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PMID:Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation. 806 99

Apo(a) is a low density lipoprotein homologous to plasminogen and has been shown to be involved in coronary atherosclerosis. In the present paper we will try to analyze the interesting evolutionary pattern of Apo(a). The plasminogen gene contains 5 cysteine-rich sequences, called kringles, followed by a protease domain. Apo(a), probably arisen by duplication of an ancestral plasminogen gene, contains many tandemly repeated copies of a sequence domain similar to the fourth kringle of plasminogen, 37 in human and at least 10 in the partially sequenced gene of rhesus, and the protease domain. We have found that the upstream kringles of apo(a) undergo Molecular Drive-like processes that produce high intraspecies similarity, whereas the downstream kringles evolve in a molecular clock-like manner and show an high interspecies sequence similarity. The latter regions are obviously suitable for dating the duplication event by which Apo(a) arose from plasminogen, but only if they evolve at the same rate in the two genes. Thus, we propose a "Molecular Clock Test" for assessing whether the comparison of two paralogous genes (or gene regions) can give reliable information on the dating of their origin by duplication. Applying this test to the kringle-4 domain of apo(a) and plasminogen gene, we demonstrate that the separation between the two genes by duplication dates back at about 90 Mya immediately before the radiation of mammals.
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PMID:The peculiar evolution of apolipoprotein(a) in human and rhesus macaque. 813 62


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