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) is an LDL-like lipoprotein which contains an additional apolipoprotein called apo(a). Apo(a) exhibits a significant size polymorphism and its size is inversely correlated with plasma Lp(a) levels. We investigated the distribution of different apo(a) isoproteins in lipoprotein density fractions. Fasting plasma samples were subjected to non-equilibrium density gradient ultracentrifugation. After SDS-PAGE and anti-apo(a) immunoblotting, apo(a) concentrations in individual density fractions were evaluated by densitometry. In series I, analysis of selected density fractions from 35 coronary heart disease (CHD) patients demonstrated that although most of the apo(a) was present in the Lp(a) density range, apo(a) was consistently found in both the VLDL and IDL fractions as well. In series II, density fractions from 9 normolipidemic subjects with 6 different apo(a) isoproteins were evaluated. A strong association between the size of the apo(a) isoprotein and the density of the associated Lp(a) particle was established (r = 0.976, P less than 0.001). Lp(a) densities ranged from 1.057 g/ml for the B isoprotein to 1.09 g/ml for the S5 isoprotein. Overall, 75% of the total apo(a) was detected in the Lp(a) density range (d = 1.05-1.12 g/ml), with 9% and 10% in the LDL (d = 1.019-1.05 g/ml) and HDL (d = 1.12-1.21 g/ml) fractions, respectively. VLDL contained an average of 4% of the total apo(a) in fasting normolipidemic plasma. Two hypertriglyceridemic subjects had substantially greater amounts of apo(a) in the fasting triglyceride-rich fraction. The results of this study indicate that the size of the apo(a) isoprotein strongly influences the density of its associated Lp(a) particle and that apo(a) is consistently found in the triglyceride-rich lipoproteins of fasting plasma.
Atherosclerosis 1992 Jun
PMID:Correlation of apolipoprotein(a) isoproteins with Lp(a) density and distribution in fasting plasma. 138 58

Lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for atherosclerosis. Lp(a) consists of a LDL-like moiety with an additional glycoprotein, apo(a), linked to apolipoprotein B-100. Apo(a) has a high homology with plasminogen (Pg). In vivo, Pg is activated on a fibrin surface by tissue Pg activator (tPA). We prepared Lp(a) from plasma by sequential ultracentrifugation followed by lysine-sepharose affinity chromatography. We found that a changing (donor dependent) fraction of the Lp(a) did not bind to lysine-sepharose. This fraction, designated Lp(a)lys-, was further purified using gel filtration. Bound Lp(a) [Lp(a)lys+] was eluted with 0.2 M EACA. Apo(a) isoforms in both fractions were identical. In contrast Lp(a)lys+ inhibited Pg activation by tPA in vitro (IC50% 20 mg/l), whereas Lp(a)lys- did not. In addition Lp(a)lys- did not bind to CNBr-digested fibrinogen whereas Lp(a)lys+ did (Kd, app = 0.2 nM). Therefore we conclude that a changing donor dependent fraction of human plasma Lp(a) does not inhibit Pg activation in vitro and does not bind to CNBr-digested fibrinogen.
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PMID:Lysine-binding heterogeneity of Lp(a): consequences for fibrin binding and inhibition of plasminogen activation. 141 65

Patients with end-stage renal failure (ESRF) on renal replacement therapy are at significantly increased risk of cardiovascular disease. To determine whether altered concentrations of apolipoprotein(a) (apo(a)), the plasminogen-like protein moiety of the atherogenic particle lipoprotein(a), contributed to this increased risk, apo(a) concentrations were measured in 48 non-diabetic patients with ESRF treated by continuous ambulatory peritoneal dialysis (CAPD) therapy and compared with 65 controls. Apo(a) concentration was increased in CAPD patients compared to controls (geometric mean 419 units/l versus 137 units/l; ratio of means 3.06 (95% CI 1.95-4.80). We conclude that CAPD patients have increased apo(a) concentrations which may contribute to their increased risk of cardiovascular disease.
Atherosclerosis 1992 Mar
PMID:Increased serum apolipoprotein(a) in patients with chronic renal failure treated with continuous ambulatory peritoneal dialysis. 159 3

The role of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) isoforms in symptomatic peripheral atherosclerosis was studied in 100 randomly selected middle-aged (45-69 years) men with intermittent claudication (IC) and 100 randomly selected healthy control (C) subjects. IC and C subjects were matched pairwise for sex, age, and smoking habits. Plasma Lp(a) concentrations were significantly higher in IC subjects, with a median value of 20.12 mg/dl, compared with 11.11 mg/dl in C subjects (p less than 0.0009). The elevated Lp(a) concentration was to a great extent due to a significant difference in the frequency distribution of apo(a) isoforms between IC and C subjects (p less than 0.029). Low-molecular-weight apo(a) isoforms were more prevalent in IC than C subjects. Also, IC subjects with apo(a) S2 and S3 phenotypes had higher Lp(a) concentrations than control subjects with the same phenotypes: S2:60.70 mg/dl (IC) and 48.69 mg/dl (C), p less than 0.038; and S3: 30.18 mg/dl (IC) and 12.01 mg/dl (C), p less than 0.042, so other still-unknown factors, genetic or nongenetic, may be important. Stepwise logistic regression analysis demonstrated that Lp(a) concentration contributed significantly (p less than 0.0002) to IC, independent of age, smoking, hypertension, diabetes mellitus, plasma total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apo B, and plasma total triglycerides. Apo(a) isoforms grouped according to molecular weight were also independent of the above risk factors associated (p = 0.016) with the occurrence of IC because of their low-molecular-weight but were not independent of Lp(a) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Significant association between low-molecular-weight apolipoprotein(a) isoforms and intermittent claudication. 163 87

The cynomolgus macaque was used as a model to study lipoprotein(a) (Lp(a)). Antibodies to Lp(a) were used in Ouchterlony and Western blot analysis to show that cynomolgus monkey and human Lp(a) were similar immunochemically. Monkey Lp(a) levels were measured by a quantitative sandwich enzyme-linked immunosorbent assay in 117 animals, and Lp(a) varied in concentration from 1 to 64 mg/dl. Individual monkeys had apo(a) glycoprotein sizes as either single- or double-band phenotypes that ranged from 400 to 750 kDa. Monkey apo(a) transcript lengths varied from 8.5 to 13.6 kilobases. The Lp(a) concentration, apo(a) glycoprotein size, and apo(a) transcript length distributions were similar to those in humans. In the monkeys, there was a very high correlation between apo(a) transcript size and apo(a) protein size (R = 0.93, p = 0.0001). This variation in apo(a) transcript and protein size was shown to be due to the number of kringle IV repeats in apo(a) mRNA and DNA. Monkey plasma Lp(a) concentrations correlated inversely with apo(a) glycoprotein size (R = 0.43, p = 0.0016) and directly with hepatic apo(a) mRNA abundance (R = 0.54, p = 0.004). Apo(a) transcript lengths did not correlate with hepatic apo(a) mRNA levels. This suggests that apo(a) size and mRNA levels have major independent effects on plasma Lp(a) concentration. In multivariate analysis, they account for up to 58% of the variability in Lp(a) concentration. In summary, these data provide insight into the regulation of Lp(a) levels and suggest that the cynomolgus monkey is a suitable model in which to study the role of Lp(a) in the pathogenesis of atherosclerosis.
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PMID:Plasma lipoprotein(a) concentration is controlled by apolipoprotein(a) (apo(a)) protein size and the abundance of hepatic apo(a) mRNA in a cynomolgus monkey model. 183 Mar 9

Lipoprotein(a) is a dimer consisting of one low density lipoprotein molecule joined by a disulfide bridge to apolipoprotein(a). Apo(a) shows a considerable structural homology to plasminogen, the zymogen of the proteolytic enzyme plasmin, which dissolves fibrin clots. Apo(a) may compete with plasminogen in several manners, but itself displays no proteolytic activity. It therefore may potentially interfere with fibrinolysis. On the other hand it may also be atherogenic, as indicated by its presence in atherosclerotic plaques. Although lipoprotein(a) consists of one molecule of LDL it does not appear to be regulated by the same mechanism as LDL. Likewise, cholesterol feeding does not appear to increase levels of Lp(a), although it does increase levels of LDL cholesterol. In addition, most lipid regulating drugs that do have an effect on lowering LDL cholesterol levels have little effect on Lp(a) thus also indicating regulation under different metabolic control. Lp(a) seems to constitute a genetic risk factor for coronary atherosclerosis which is independent of all other parameters and of exogenous factors.
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PMID:[Lipoprotein (a)--link between lipid metabolism and coagulation system?]. 183 45

Northern blotting and hybridisation with specific probes was used to detect and quantitate apolipoprotein(a) (apo(a)) mRNA in total RNA isolated from 25 human liver samples. A total of 14 different transcripts were identified suggesting that there are at least 15 different alleles at the apo(a) locus including a probable null allele. Apo(a) mRNA sizes were linearly correlated with the electrophoretic mobility of plasma apo(a) glycoprotein isoforms, and differed, in many cases, by the equivalent of one Kringle 4 unit. To investigate the relationship between apo(a) mRNA size and its concentration in the liver, and between hepatic apo(a) mRNA concentration and plasma lipoprotein(a) (Lp(a)) levels, apo(a) mRNA was quantified by densitometric scanning of autoradiograms of Northern blots. Overall, there was a significant inverse correlation between apo(a) mRNA size and its concentration in the liver, despite a marked interindividual variability in the relative amounts of similar-sized transcripts. In each heterozygous individual, the difference in concentration between the two mRNA species was determined by the difference in size. However, there was not a significant relationship between hepatic apo(a) mRNA concentration and plasma Lp(a) levels in this group. These findings emphasise the importance of mechanisms other than the rate of transcription of the apo(a) gene in the regulation of Lp(a) synthesis.
Atherosclerosis 1991 Nov
PMID:Detection and quantitation of apolipoprotein(a) mRNA in human liver and its relationship with plasma lipoprotein(a) concentration. 183 19

Lipoprotein(a) denotes cholesterol-rich particles similar to low density lipoproteins but characterized by an extra large hydrophilic glycoprotein, Apo(a), added to low density lipoproteins. Apolipoprotein(a) is bound to ApoB-100 by a disulfide bridge. Eleven different Apo(a) isoforms of varying sizes coded for by alleles at the Apo(a) gene locus on chromosome 6 have been identified, ranging in Mr between roughly 400-800 kDa. The level of lipoprotein(a) is inversely correlated with isoform size. A strong independent association between high lipoprotein(a) levels and atherosclerotic disorders is documented. Lipoprotein(a) is selectively retained in the intima and engulfed by macrophages in unmodified form. Human Apo(a) is very similar to plasminogen, which suggests that lipoprotein(a) represents a link between atherosclerosis and thrombosis.
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PMID:Lipoprotein(a), atherosclerosis and thrombosis. 184 Apr 53

Patients with insulin-dependent diabetes mellitus (IDDM) have a significantly increased risk of macrovascular disease, particularly if they have persistent proteinuria. To determine whether altered levels of apolipoprotein(a) [apo(a)], the plasminogenlike glycoprotein of the potentially atherogenic lipoprotein(a); contribute to the increased risk of atherosclerosis, apo(a) levels were measured in 107 patients with IDDM and compared with nondiabetic control subjects and male elective coronary artery graft patients. Apo(a) levels were increased in diabetic patients with microalbuminuria (geometric mean 245 U/L, 95% confidence interval [CI] 142-427, n = 30) and albuminuria (mean 196 U/L, 95% CI 97-397, n = 18) with levels comparable to patients with coronary artery disease (mean 193 U/L, 95% CI 126-298, n = 40), which were higher than in the control group (mean 107 U/L, 95% CI 85-134, n = 140; P = 0.016). Apo(a) levels in diabetic patients without microalbuminuria (mean 86 U/L, 95% CI 63-116, n = 59) were comparable with the control population and less than in those with microalbuminuria (P less than 0.001) and albuminuria (P = 0.014). The elevated apo(a) levels found in patients with IDDM and increased urinary albumin loss may contribute to their heightened risk of macrovascular disease.
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PMID:Increased plasma apolipoprotein(a) levels in IDDM patients with microalbuminuria. 204 Mar 96

Plasma Lp(a) levels correlate with atherosclerosis susceptibility. This lipoprotein consists of an LDL-like particle attached to a large glycoprotein called apo(a). Apo(a) is a complex glycoprotein containing multiple Kringle domains, found to be highly homologous to plasminogen Kringle IV, and a single Kringle domain homologous to plasminogen Kringle V. Lp(a) levels appear to be inversely correlated with apo(a) size in a given individual. In this study, we have used probes specific to the Kringles IV and V domains of apo(a) cDNA in quantitative Southern blotting analysis. By this method, we have determined the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene of 53 unrelated individuals with different plasma concentrations of Lp(a). This ratio was found to be inversely correlated with log Lp(a) levels (r = -0.90, P less than 0.0001) and directly correlated with apo(a) apparent molecular weight (Mr) (r = 0.79, P less than 0.0001). In summary, by showing that Lp(a) concentrations and apo(a) apparent size are highly correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene, we provide a DNA marker for this atherosclerosis risk factor as well as an important insight into the genetic mechanism regulating Lp(a) levels.
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PMID:Plasma Ip(a) concentration is inversely correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene. 255 54


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