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Biomedical subjects

A M Scanu

Publications and source records attributed to A M Scanu.

At least 91 records · Page 5Linked to original sources
PubMed1991

Lipoprotein(a): nonhuman primate models.

Lipoprotein(a) [Lp(a)] is a low density lipoprotein which has apo(a) disulfide-linked to apoB100. Apo(a) has recently been shown to have a striking homology with plasminogen, a knowledge that has stimulated a lot of interest in the mechanism of atherogenicity and thrombogenicity of this lipoprotein particle. Several studies have documented the presence of Lp(a) in nonhuman primates with particular reference to the rhesus monkeys and baboons. The Lp(a) of rhesus monkey is structurally very similar to that of humans, except for the absence of kringle V and the amino acid composition of the catalytic region. The Lp(a) of nonhuman primates, like their human counterparts, exhibit a wide range of interindividual plasma levels and also a wide size polymorphism of apo(a). Nonhuman primates appear to represent a good model for the study of the structure and biology of Lp(a).

Animals↗
PubMed1991

Lipoprotein(a) levels in black and white children and adolescents with IDDM.

OBJECTIVE: To examine the relationship between levels of lipoprotein(a) [Lp(a)], diabetes, and glycemic control in white and black nondiabetic control and insulin-dependent diabetic (IDDM) children and adolescents, fasting blood analyses were conducted on a subject sample drawn from referral-based diabetes and endocrine clinics and a primary-care general pediatric clinic. RESEARCH DESIGN AND METHODS: Thirty-six white and 16 black children with IDDM who volunteered to participate in this study were compared with 30 white and 42 black nondiabetic control children. RESULTS: Lp(a) protein levels were significantly higher (P less than 0.05) in both groups of black children compared with whites (black vs. white nondiabetic children 6.8 +/- 0.95 vs. 3.1 +/- 0.68 mg/dl and black vs. white diabetic children 7.5 +/- 1.52 vs. 3.0 +/- 0.64 mg/dl). Lp(a) protein levels directly correlated with the level of glycosylated hemoglobin (r = 0.46, P less than 0.01) in white diabetic children but not in black diabetic children. Well-controlled white diabetic children (n = 12, glycosylated hemoglobin less than 10%) had a mean Lp(a) protein level of 1.4 +/- 0.3 mg/dl compared with poorly controlled white diabetic children (n = 10, glycosylated hemoglobin greater than 13%) whose mean Lp(a) protein level was 5.7 +/- 1.7 mg/dl (P less than 0.01). CONCLUSIONS: We conclude that circulating levels of Lp(a) protein are increased in hyperglycemia. A genetically determined elevated level of Lp(a) is a risk factor for atherosclerotic disease in white and Asian adults. Elevated Lp(a) should be investigated as an independent risk factor for atherosclerotic disease in IDDM. It could prove to be an additional mechanism for the development of diabetic complications in selected populations.

Adolescent↗
PubMed1991

Relationship between apo[a] isoforms and Lp[a] density in subjects with different apo[a] phenotype: a study before and after a fatty meal.

Plasma Lp[a] levels and apo[a] isoform distribution among lipoproteins isolated by density gradient ultracentrifugation were studied in subjects with one-band or two-band apo[a] phenotypes as assessed by gradient gel electrophoresis before and after an oral fat load. There were no significant differences in the ultracentrifugal profile between fasting plasma and postprandial plasma that was freed of triglyceride-rich particles (TRP). One-band phenotypes exhibited a single symmetrical peak in the density gradient, whereas two-band phenotypes exhibited a multi-modal distribution. Low molecular weight apo[a] isoforms were preferentially associated with low density Lp[a] whereas high molecular weight apo[a] isoforms were found with high density Lp[a] particles. Feeding a high fat meal caused no significant increase in the total plasma level of Lp[a]. However, the isolated TRP contained the apoB-100-apo[a] complex in a quantity that represented only about 1% of its total amount in the fasting plasma. In all cases the apo[a] isoforms present in TRP were also present in the fasting plasma; however, in the two-band apo[a] phenotypes the ratio of the slow over the fast migrating band was in all cases about eightfold higher in TRP than in the fasting plasma. These observations indicate that postprandially a small percentage of apoB-100-apo[a] associates with TRP and suggest that this complex may derive from de novo synthesis rather than from a pre-existing Lp[a] plasma pool. The liver would be the source of the complex due to the presence in the latter of apoB-100.

Adult↗
PubMed1991

Physiopathology of plasma lipoprotein metabolism.

The metabolism of plasma lipoproteins is under the regulation of several factors which involve apolipoproteins, lipid-modifying enzymes, lipid transfer proteins, and cell membrane receptors. The genes of most of these proteins have been defined and several mutants of these proteins also identified. Studies of these mutants have provided important new insights into the molecular basis of the abnormalities of lipoprotein metabolism and also a better understanding of the mechanisms involved in secondary dyslipoproteinemias inclusive of those occurring in renal disorders.

Humans↗
PubMed1990

Lipoprotein(a).

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Apolipoproteins A↗
PubMed1990

Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency.

We have recently identified a family of rhesus monkeys with members exhibiting a spontaneous hypercholesterolemia associated with a low density lipoprotein receptor (LDLR) deficiency. By using the polymerase chain reaction, we now show that the affected monkeys are heterozygous for a nonsense mutation in exon 6 of the LDLR gene. This mutation changes the sequence of the codon for amino acid 284 (tryptophan) from TGG to TAG, thereby generating a nonsense codon potentially resulting in a truncated 283-amino acid protein, which needs documentation, however. This G----A mutation also creates a site for the restriction endonuclease Spe I. Using this site as a marker for this nonsense mutation, we have shown that the mutation is present in all of the affected members of the pedigree and absent in unaffected members and that the mutation segregates with the phenotype of spontaneous hypercholesterolemia through three generations. Quantitative analyses of RNA obtained from liver biopsies show that the abundance of the LDLR RNA is also reduced by about 50%. Thus, we have identified a primate model for human familial hypercholesterolemia which will be useful for studying the relationship between the LDLR and lipoprotein metabolism and for assessing the efficacy of diets and drugs in the treatment of human familial hypercholesterolemia.

Animals↗
PubMed1990

Rhesus monkey model of familial hypercholesterolemia: relation between plasma Lp[a] levels, apo[a] isoforms, and LDL-receptor function.

We previously described a family of rhesus monkeys in which three out of six members had a spontaneous hypercholesterolemia related to a decrease in number of low density lipoprotein receptors (LDL-R) (Scanu et al. 1988. J. Lipid Res. 29: 1671-1681). During the current work an additional female normocholesterolemic offspring was generated from the mating of the original dam and sire. Moreover, from the breeding of one of the affected male offspring with six unrelated normocholesterolemic female monkeys, eight offspring were generated of which three were hypercholesterolemic on a cholesterol-free diet and exhibited the same degree of LDL-R deficiency as shown by studies in skin fibroblast cultures. All of the animals studied had levels of plasma lipoprotein[a] protein ranging between 1.0 mg/dl and 57.5 mg/dl that were only weakly correlated with total plasma cholesterol, LDL cholesterol, and apoB. LDL-R deficiency correlated with plasma LDL but not Lp[a]. A 7 week fat challenge (16.5% lard, 0.64% cholesterol) that raised the plasma LDL levels markedly had no effect on plasma Lp[a]. Animals with the single band apo[a] phenotype moving on SDS-PAGE faster than apoB-100 exhibited a tendency for high plasma Lp[a] levels which, however, varied widely. Wide variations in Lp[a] levels were also noted with the other apo[a] phenotypes. Taken together our results demonstrate a successful transmission to second generation animals of the LDL-R deficiency phenotype and provide evidence that this phenotype correlates well with plasma LDL levels but not Lp[a]. Our data also suggest that the apo[a] gene is only partially involved in the regulation of the plasma Lp[a] levels.

Animals↗
PubMed1990

Solubility, immunochemical, and lipoprotein binding properties of apoB-100-apo[a], the protein moiety of lipoprotein[a].

The protein moiety of Lp[a] consisting of apoB and apo[a] covalently linked to each other, once freed of lipids by delipidation at pH 8.0 with mixtures of diethyl ether and ethanol, is freely water-soluble at pH values above 6.4. This is in contrast to apoB which, if prepared by similar delipidation techniques, is only soluble at alkaline pH, indicating that the coupling of the carbohydrate-rich apo[a] to apoB confers water solubility to this apolipoprotein that it does not possess on its own. When probed in a sandwich ELISA with antibodies specific to apo[a], the results suggest that some apo[a] epitopes in Lp[a] are masked by lipid but are freely accessible to antibodies in the lipid-free apoB-apo[a] complex. Examination of apoB-apo[a] with an ELISA specific for apoB showed a decreased and altered immunoreactivity of apoB when compared to either low density lipoprotein (LDL) or Lp[a]. These results are consistent with a model in which the hydrophobic lipid binding domains of apoB in apoB-apo[a] self-associate and are shielded from the aqueous environment by the hydrophilic portions of apoB and by an envelope of apo[a]. The apoB-apo[a] complex has lipophilic properties as shown by its interaction with the phospholipid-stabilized triglyceride emulsion, Intralipid. In addition, it has an avidity for all types of lipoproteins although displaying a preference for triglyceride-rich particles. In the presence of plasma, the interaction of apoB-apo[a] with all lipoproteins is reduced. Neither iodinated apo[a] nor iodinated Lp[a] nor LDL had an affinity for lipoproteins, suggesting that the lipophilic properties of apoB-apo[a] are probably due to apoB since apo[a] is rather hydrophilic and is unable to bind to lipids. Thus, the apoB-apo[a] complex has amphipathic properties with apo[a] providing the hydrophilic capacity to interact with the aqueous environment and apoB providing the hydrophobic interactions necessary to bind lipids.

Apolipoproteins A↗
PubMed1990

Lipoprotein(a): a genetically determined cardiovascular pathogen in search of a function.

Lipoprotein(a) (Lp(a)) is a genetically-determined lipoprotein variant with a lipid composition similar to that of low-density lipoproteins (LDL) and a protein moiety consisting of apolipoprotein B-100 (apoB100) linked covalently to apolipoprotein(a) (apo(a)), which is a glycoprotein with a striking structural similarity to plasminogen. One of the characteristics of plasma Lp(a) is to vary widely in concentration and to be heterogeneous in size and density. Apo(a) also exhibits an important size heterogeneity that is related to the number of kringle 4 domains under the control of the apo(a) gene. Epidemiologic studies have linked high plasma levels of Lp(a) to an increased prevalence of atherosclerotic cardiovascular disease by yet undefined mechanisms. It is possible that because of its unique structural features, Lp(a) may have both atherogenic and thrombogenic actions.

Cardiovascular Diseases↗
PubMed1989

A potential basis for the thrombotic risks associated with lipoprotein(a).

Lipoprotein(a) (Lp(a)) has been strongly linked with atherosclerosis and is an independent risk factor for myocardial infarction. Distinguishing Lp(a) from other low-density lipoprotein particles is its content of a unique apoprotein, apo(a). The recently described sequence of apo(a) indicates a remarkable homology with plasminogen, the zymogen of the primary thrombolytic enzyme, plasmin. Lp(a) may contain 37 or more disulphide-looped kringle structures, which are 75-85% identical to the fourth kringle of plasminogen. Plasminogen receptors are widely distributed on blood cells and are present at extremely high density on endothelial cells. These receptors promote thrombolysis by accelerating plasminogen activation and protecting plasmin from inhibition. If, by molecular mimicry, Lp(a) competes with plasminogen for receptors, then thrombolysis would be inhibited and thrombosis promoted. Here we provide support for such a mechanism being responsible for the thrombotic risks associated with elevated Lp(a) by demonstrating that Lp(a) inhibits plasminogen binding to cells.

Binding, Competitive↗
PubMed1989

Apolipoprotein B-100 of plasma low density lipoproteins undergoes proteolysis by contact activation factors when plasma is treated with dextran sulfate-500-MgCl2.

Human plasma low density lipoproteins (LDL) isolated by ultracentrifugation showed a single band corresponding to apolipoprotein B-100 (apoB-100) by SDS-gradient gel electrophoresis (GGE). In turn, apoB-100 of LDL precipitated from plasma by dextran sulfate-500 (DS)-MgCl2 exhibited several bands indicative of a degradative process. The degradation was more extensive at 0 degrees C than at either 23 degrees C or 37 degrees C, and appeared to be related to a protease activity that cleaved both the synthetic peptide, Z-Phe-Arg-7-amido-4-methylcoumarin (Z-Phe-Arg-AMC) and apoB-100. Proteolysis was proportional to the DS added to the plasma, was prevented by the kallikrein inhibitor, D-Phe-L-Phe-L-Arg-CHCl2, and was significantly decreased in plasma specimens of patients with either factor XII or prekalikrein deficiency. LDL pre-purified by ultracentrifugation and then precipitated by DS in the absence of plasma exhibited no proteolysis. However, proteolysis was observed when LDL interacted with kallikrein. The two main apolipoproteins of HDL3, apoA-I and apoA-II, were not affected by this proteolytic process. We interpret the results to indicate that the negatively charged surface provided by DS accelerates in plasma the autoactivation of factor XII and the activation of prekallikrein, resulting in an increase of the effective concentration of kallikrein and possibly other proteases and proteolysis of LDL-apoB-100. The higher degree of the DS-induced proteolysis of apoB-100 at 0 degrees C than at 23 degrees C is likely the consequence of enhanced autoactivation of factor XII and a decreased efficiency of plasma inhibitors, such as C1-inhibitor. We speculate that the proteolysis of apoB-100 induced by DS is not limited to this polyanion, but may also be the property of other negatively charged agents, particularly at cold temperatures.

Apolipoprotein B-100↗
PubMed1989

Enzyme-linked immunoassay for Lp[a].

Based on our findings that rabbit antisera raised against human Lp[a] or apo[a] have the potential to cross-react with plasminogen, and in some cases have nearly equal affinities for plasminogen and Lp[a], we have developed an assay for plasma Lp[a] based on a "sandwich" ELISA that is insensitive to the presence of plasminogen. This was accomplished through the use of anti-apo[a] as a capture antibody and quantitation of the bound Lp[a], i.e., the apoB-100-apo[a] complex, with an anti-apoB antibody. Although apo[a] is heterogeneous in size, all Lp[a] particles tested, either in pure form or contained in whole plasma, gave parallel dose-response curves and were immunologically equivalent. However, when purified Lp[a] particles with different apo[a] isoforms were studied, those having larger isoforms were, on a weight basis, less reactive than those having a smaller size. Nearly equivalent reactivity was observed when protein concentration was expressed on a molar basis. The distribution of Lp[a] in a population of 84 subjects was skewed with one-third of the individuals having less than 1 mg/dl Lp[a] protein. All subjects tested had measurable concentrations of Lp[a] with a lower limit of detection of 0.030 mg/dl Lp[a] protein. The mean level was 3.2 mg/dl with a range of 0.045 to 13.3 mg/dl. These studies demonstrate the successful development of an ELISA for Lp[a] protein that is insensitive to the presence of plasminogen; that heterogeneity of Lp[a] and apo[a] are an important source of variation in the assay; and the need for an appropriate Lp[a] standard in order to minimize this variation.

Adolescent↗