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Biomedical subjects

A M Scanu

Publications and source records attributed to A M Scanu.

At least 19 recordsLinked to original sources
PubMed1992

Lipoprotein(a): its inheritance and molecular basis of its atherothrombotic role.

Lipoprotein(a) or Lp(a), is a member of the plasma lipoproteins with general properties of LDL but with a protein moiety represented by apoB100 disulfide linked to apolipoprotein(a) or apo(a). Apo(a) is polymorphic in size; at present a total of 11 isoforms have been reported, but more are likely to be identified in view of the fact that at least 19 alleles of the apo(a) gene have recently been reported. There are remarkable variations in the plasma Lp(a) levels; but uncertainties still exist about the factors responsible for this variability. High plasma Lp(a) levels have been associated with an increased incidence of cardiovascular disease, mainly based on epidemiological evidence. Both atherogenic and thrombogenic potentials have been suggested; the first attributable to the LDL-like properties of Lp(a) and the other to the plasminogen-like characteristics of apo(a). From the mechanistic viewpoint in vitro studies suggest that the thrombogenic action may occur at the level of the endothelium whereas Lp(a) that localizes in the sub-endothelial intima is expected to undergo complexation with matrix components and favor the formation of the atherosclerotic plaque. How Lp(a) polymorphism relates to the postulated cardiovascular pathogenicity of this lipoprotein remains to be established.

Arteriosclerosis↗
PubMed1992

Lipoprotein(a). A genetic risk factor for premature coronary heart disease.

Lipoprotein(a) (Lp[a]) can be defined as a lipoprotein particle having as a protein moiety apolipoprotein B-100 (the protein associated with low-density lipoprotein) disulfide-linked to apolipoprotein(a), the distinctive glycoprotein of Lp(a) that is homologous to plasminogen. Several forms of Lp(a) occur in the circulation. This polymorphism is related to the apolipoprotein(a) size heterogeneity that is controlled by the several alleles of the apolipoprotein(a) gene. High plasma levels of Lp(a) have been correlated with an increased risk for atherothrombotic cardiovascular disease by a mechanism that is as yet undefined. Pathogenicity may also derive from Lp(a) particles that have been modified by events believed to occur when Lp(a), after traversing the artery endothelium, reaches the intima. Aside from several promising leads, there are no universally accepted ways to lower high plasma Lp(a) levels. At this time, it is best to target efforts toward the modifiable risk factors by using appropriate diets and exercise programs and, whenever necessary, drug therapy.

Animals↗
PubMed1992

Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages.

Increased plasma levels of the apoB-100-containing lipoprotein(a) (Lp(a)) are associated with an increased risk for atherosclerosis and myocardial infarction, but the mechanisms by which lipoprotein(a) may accelerate these processes remain obscure. In this study we have investigated the impact of the association of apoprotein(a) with the low density lipoprotein (LDL)-like Lp(a) particle upon specificity of receptor recognition after lipoprotein modification by malondialdehyde or transition metal-induced oxidation. We have determined that radioiodination labels both apoprotein components of Lp(a), that malondialdehyde modification produces an anionic lipoprotein comparable to native Lp(a) in Stokes' radius, and that N,N'-disubstituted 1-amino-3-iminopropene derivatives preferentially cross-link apoprotein(a) to apoB-100 protein. Like LDL, native Lp(a) is recognized in human monocyte-macrophages by the LDL receptor. Like LDL, progressive modification of Lp(a) by malondialdehyde abolishes lipoprotein recognition by the LDL receptor and produces uptake and hydrolysis by the scavenger receptor of human monocyte-macrophages. We propose that intimal retention of Lp(a) by extracellular components of the atherosclerotic reaction places the lipoprotein in a microenvironment favoring subsequent peroxidative modification. The chronic production of lipid peroxide-modified Lp(a) together with unmitigated cellular clearance by scavenger receptors may contribute to the accumulation of lipoprotein-derived lipid in macrophage-derived foam cells of the atherosclerotic reaction.

Cells, Cultured↗
PubMed1992

Comparative binding and degradation of lipoprotein(a) and low density lipoprotein by human monocyte-derived macrophages.

The binding and degradation of equimolar concentrations of lipoprotein(a) (Lp(a)) and low density lipoprotein (LDL) isolated from the same individual were studied in primary cultures of human monocyte-derived macrophages (HMDM). At 4 degrees C, LDL receptor-mediated binding of both Lp(a) and LDL was of low affinity, being 0.8 and 0.23 microM, respectively. Competitive binding studies indicated that the binding of Lp(a) to HMDM was competed 63% by excess LDL. In contrast to the 4 degrees C binding data, the degradation of Lp(a) at 37 degrees C was mainly nonspecific because the amount of Lp(a) processed by the LDL receptor pathway in 5 h was 17% that of LDL. According to pulse-chase experiments, this phenomenon may be accounted for by the facts that less Lp(a) is bound to HMDM at 37 degrees C and that Lp(a) has a lower intrinsic degradation rate and was not due to increased intracellular accumulation or retroendocytosis of the lipoprotein. Degradation of both lipoproteins was primarily lysosomal and only modestly affected by up- or down-regulation of the LDL receptor. The rate of retroendocytosis in HMDM was approximately equal to the degradation rate and appeared to be independent of the type of lipoprotein used, up- or down-regulation of the LDL receptor, or the presence of the lysosomotropic agent chloroquine. Overall, the results indicate that HMDM degrade Lp(a) mainly via a nonspecific pathway with only 25% of total Lp(a) degradation occurring through the LDL receptor pathway. As both 37 degrees C degradation and 4 degrees C binding of LDL are mainly LDL receptor specific, the different metabolic behavior observed at 37 degrees C suggests that Lp(a) undergoes temperature-induced conformational changes on cooling to 4 degrees C that allows better recognition of Lp(a) by the LDL receptor at a temperature lower than the physiological temperature of 37 degrees C. How apo(a) affects these structural changes remains to be established.

Binding, Competitive↗
PubMed1992

Lp(a): a link between thrombosis and atherosclerosis.

Lipoprotein(a), or Lp(a), is a lipoprotein having lipid composition similar to that of LDL, but a protein moiety consisting of ApoB 100 linked by disulfide bridge to apo(a), a glycoprotein with structural similarity to plasminogen. Lp(a) can be both atherogenic and thrombogenic. These two actions are likely to be mutually operative, a fact that on a molar basis makes Lp(a) more of a cardiovascular pathogen than LDL.

Adult↗
PubMed1992

Plasma lipoprotein (a) protein concentration and coronary artery disease in black patients compared with white patients.

PURPOSE: This study examines the relation between lipoprotein (a) protein levels and other lipid parameters and coronary artery disease in white and black patients. PATIENTS AND METHODS: Plasma lipoprotein (a) protein levels were measured prior to coronary angiography in a population of 127 white and 111 black patients. Each angiogram was given a total coronary artery disease score based on the number and severity of atherosclerotic coronary lesions. RESULTS: White and black patients exhibited no differences in total plasma cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. Black patients had higher lipoprotein (a) protein levels than white patients (8.6 versus 4.0 mg/dL; p < 0.0001). The extent and severity of coronary artery disease was the same in white and black patients. White and black patients with coronary artery disease had higher lipoprotein (a) levels than patients without coronary lesions (4.37 versus 1.99 mg/dL, p = 0.027 for white; 9.23 versus 6.87 mg/dL, p = 0.072 for black). In both groups of patients, there was a weak but significant positive correlation between lipoprotein (a) protein levels and coronary artery disease score. CONCLUSION: Lipoprotein (a) is higher in patients with coronary artery disease. Black patients have higher plasma lipoprotein (a) protein levels than white patients and a comparable degree of coronary artery disease. It follows that the cardiovascular pathogenicity of lipoprotein (a) is not significantly greater in black patients despite higher lipoprotein (a) levels.

Black or African American↗
PubMed1992

Postprandial lipoprotein(a) response to a single meal containing either saturated or omega-3 polyunsaturated fatty acids in subjects with hypoalphalipoproteinemia.

We have recently reported that the apolipoprotein (apo) B-100-apo(a) complex, the protein moiety of lipoprotein(a) [Lp(a)], has a high affinity for triglyceride(TG)-rich particles (TRP) and that this complex can affiliate with endogenous TG-rich lipoproteins. To shed more light on the apo B-100-apo(a) complex associated with plasma TRP during postprandial lipidemia, we fed five male subjects presenting with primary hypoalphalipoproteinemia (HP) and four male controls a single fat meal (60 g/m2) containing saturated fatty acids (SFA) and, 6 weeks later, an isocaloric meal containing omega-3 polyunsaturated fatty acids. The subjects were phenotyped for plasma Lp(a) and apo C-III levels, apo(a) and apo E isoforms, and lipoprotein lipase and hepatic lipase activities. Vitamin A was included in the meal as a marker of intestinally derived TRP. Following the SFA meal, three of the HP subjects showed a decrease in plasma levels of Lp(a) that lasted 10 to 12 hours in the presence of an increased hypertriglyceridemic response. Two HP subjects who had low preprandial lipoprotein lipase activity and elevated plasma apo C-III levels showed an increase in plasma Lp(a) levels along with the hypertriglyceridemic excursion. However, in all cases, inclusive of the controls, there was an elevation in plasma levels of TRP of Sf greater than 1,000 that contained apo B-100-apo(a) 6 to 8 hours after the meal. This TRP excursion appeared not to be related to the basal levels of plasma Lp(a), high-density lipoprotein (HDL) cholesterol, TGs, or apo(a) and apo E isoforms, and it did not coincide with the retinyl ester peak.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Expression and purification of kringle 4-type 2 of human apolipoprotein (a) in Escherichia coli.

The most frequently occurring kringle 4 domain of human apolipoprotein (a), Kringle 4-subtype 2 (K4(2)), was expressed as a fusion protein with the maltose binding protein in Escherichia coli using the "tac" promoter. Although the fusion protein was expressed without a signal sequence, 25% was secreted into the periplasmic space; the remainder was found associated with the soluble cytosolic fraction. The fusion protein was readily isolated from whole cell lysate by amylose agarose affinity chromatography. Although a factor Xa cleavage site was engineered into the fusion protein, it was found that release of the K4(2) protein was most conveniently achieved by proteolysis with subtilisin A. The cleavage product produced in this way was shown to be intact K4(2) with only the first three amino acid residues of the leading flanking peptide missing, as judged by N-terminal sequence analysis. K4(2) was isolated from the hydrolysate by FPLC on a Mono-Q column with a yield of 170 +/- 30 micrograms/g wet cells. The resulting protein was monomeric in phosphate-buffered saline as judged by size-exclusion chromatography and appeared to be folded as shown by spectroscopic and immunological assays. The recombinant K4(2) did not bind to either lysine- or proline-Sepharose, suggesting that the ligand binding activities of lipoprotein (a) may reside in the other kringle domains of apolipoprotein (a).

ATP-Binding Cassette Transporters↗
PubMed1992

Lipoprotein(a). Link between structure and pathology.

It is now established that high plasma levels of lipoprotein(a) are associated with an increased risk of atherosclerotic cardiovascular disease. However, the mechanisms underlying this increased risk have not been elucidated. Lipoprotein(a) represents a class of lipoprotein particles having a cholesteryl ester-rich low-density lipoprotein (LDL)-like structure with a protein moiety represented by apolipoprotein B100 covalently linked to apolipoprotein(a), the specific marker of lipoprotein(a). Lipoprotein(a) particles with a triglyceride-rich core have also been described. Apolipoprotein(a) is a glycoprotein containing about 30% carbohydrates by weight, with a polypeptide chain highly polymorphic in size (300-700 kDa) and structurally similar to plasminogen. There appears to be a relation between apolipoprotein(a) size and lipoprotein(a) species. From a number of studies, it is becoming apparent that lipoprotein(a) can transverse the endothelium and accumulate in the arterial initima either extra- or intracellularly. Immunochemical evidence has also indicated that apolipoprotein(a) in the artery wall is colocalized with fibrin(ogen), suggesting that this complexation may have an atherogenic potential by promoting the transformation of resident macrophages into foam cells. This might also occur by the chemical modification of lipoprotein(a) by the action of either oxygen-free radicals, malondialdehyde, or interactions with matrix components. These findings invite the speculation that much of the apolipoprotein B detected in atherosclerotic lesions is contributed by lipoprotein(a). The role that lipoprotein(a) size and density heterogeneity and apolipoprotein(a) polymorphism might play in the intima accumulation of apolipoprotein B is not established.

Apolipoproteins A↗
PubMed1992

Genetic basis and pathophysiological implications of high plasma Lp(a) levels.

Lipoprotein(a) or Lp(a) is a genetic variant of plasma low density lipoproteins (LDL) containing apoB100 covalently linked to apolipoprotein(a) or apo(a), the specific marker of Lp(a). Lp(a) is heterogeneous in size and density, accounting in part for the marked size polymorphism of apo(a), 300 to 800 kDa. The apo(a) size polymorphism is related to the different number of kringle repeats which are structurally similar although not identical to the kringle 4 of plasminogen. Recent studies on a genomic level have indicated that the apo(a) gene contains at least 19 different alleles varying in length between 48 and 190 kb, partially impacting on the plasma levels of Lp(a). High plasma levels of Lp(a) have been found to be associated with an increased prevalence of premature atherosclerotic cardiovascular disease by mechanism(s) yet to be established. Both atherogenic and thrombogenic potentials have been postulated and have been related to the LDL-like and plasminogen-like properties of Lp(a), respectively.

Alleles↗
PubMed1992

Attenuation of immunologic reactivity of lipoprotein(a) by thiols and cysteine-containing compounds. Structural implications.

Samples of human plasma having lipoprotein(a) (Lp[a]) protein levels between 5 and 15 mg/dl and a single apolipoprotein(a) (apo[a]) isoform were incubated in vitro at pH 7.7 with various concentrations (1-20 mM) of N-acetylcysteine, homocysteine, 2-mercaptoethanol (2ME), and dithiothreitol (DTT) for 1 hour at 37 degrees C under a nitrogen atmosphere. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by immunoblot analyses using a polyclonal antibody specific for apo(a) showed a progressive decrease in apo(a) immunoreactivity as a function of reductant concentration. This decrease of apo(a) immunoreactivity was corroborated by enzyme-linked immunosorbent assay (ELISA) using anti-apo(a) as the capture antibody and either anti-apo B or anti-apo(a) as the developing antibody. In turn, there was no significant decrease in the immunoreactivity of apo B-100, as assessed by ELISA using anti-apo B as both the capture and the detecting antibody. In the case of high concentrations of DTT the plasma samples had to be diluted to prevent gel formation on addition of the reductant. A progressive drop in immunoreactivity as a function of reagent concentration was also observed in pure preparations of Lp(a) incubated with the reducing agents at pH 7.7. At equivalent stoichiometries the changes were more marked than those observed with whole plasma, suggesting a quenching effect by the plasma proteins on the activity of the reductants. The changes in immunoreactivity were attended by dissociation of apo(a) from Lp(a) as assessed by Western blotting. This dissociation, which we interpret as the result of cleavage of the interchain disulfide bond(s), was complete at 5 mM DTT and 100 mM 2ME.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1991

Lipoprotein(a) and atherosclerosis.

Lipoprotein(a) [Lp(a)], a lipoprotein variant, was relegated for almost 25 years to the study of a few specialists. During the past 3 to 4 years, however, there has been a tremendous upsurge of interest in Lp(a), primarily because of multidisciplinary efforts in structural and molecular biology. Findings emerging from these efforts include the following: Lp(a) represents a cholesteryl-ester, low-density-lipoprotein (LDL)-like particle with apolipoprotein (apo) B-100 linked to apo(a); apo(a) is a glycoprotein coded by a single gene locus on the long arm of chromosome 6, which has several alleles, accounting for its remarkable size polymorphism (300 to 800 kD); apo(a) size polymorphism relates to plasma levels and density distribution of Lp(a); apo(a) is strikingly similar to plasminogen; and in vitro, Lp(a), in appropriate levels, competes for some physiologic functions of plasminogen in the coagulation and fibrinolytic cascade and may thus be thrombogenic. The LDL-like properties of Lp(a) may also confer atherogenic potential, but the mechanisms underlying this atherogenicity remain to be defined. In epidemiologic studies, high plasma Lp(a) levels have been associated with an increased incidence of atherosclerotic cardiovascular disease, especially in patients less than 60 years of age. Moreover, Lp(a) has been found as an intact particle in the arterial intima, particularly in association with atherosclerotic plaque. This finding suggests that Lp(a) can transverse the endothelium, possibly by a non-receptor-mediated process, and, at the intimal level, acquire thrombogenic and atherogenic potentials. Current information justifies the need to determine plasma Lp(a) levels in patients with a history of atherosclerotic cardiovascular disease. Unfortunately, the available techniques need to be standardized. Apolipoprotein(a) exists in isoforms of different sizes, and the importance of determining apo(a) phenotypes in clinical practice remains to be established.

Arteriosclerosis↗
PubMed1991

Tissue-type plasminogen activator binds to and is inhibited by surface-bound lipoprotein(a) and low-density lipoprotein.

Elevated levels of lipoprotein(a) [Lp(a)] are associated with an increased risk of atherothrombotic disease, but the mechanism(s) by which Lp(a) potentiates atherogenesis is unknown. The extensive homology of apolipoprotein(a) [apo(a)] to plasminogen has led us and others to postulate that Lp(a) may impair fibrinolysis. We have previously shown that Lp(a) inhibits fibrin stimulation of plasminogen activation by tissue-type plasminogen activator (t-PA); however, we and other investigators have been unable to demonstrate direct inhibition of t-PA by Lp(a) in solution. We now report that t-PA binds reversibly and saturably to surface-bound Lp(a) and to low-density lipoprotein (LDL) and that as a result of this binding activation of plasminogen by t-PA is inhibited. The catalytic efficiency (kcat/Km) of t-PA when bound to polystyrene surface-bound fibrinogen increased 2.9-fold compared to t-PA bound to control wells. When bound to surface-bound Lp(a), however, the catalytic efficiency of t-PA was reduced 9.5-fold compared to t-PA bound to control wells; likewise, by binding to surface-bound LDL, the catalytic efficiency of t-PA was reduced 16-fold compared to the control. Studies with defined monoclonal antibodies suggest that major determinants of t-PA binding are its active site, the LDL receptor binding domain of apolipoprotein B-100 (apoB-100), and apo(a). These data suggest a unique mechanism by which Lp(a) and LDL incorporated in an atheroma can inhibit endogenous fibrinolysis and thereby contribute to the genesis of atherothrombotic disease.

Antibodies, Monoclonal↗
PubMed1991

Lp(a) as a marker for coronary heart disease risk.

Lipoprotein(a) or Lp(a) represents a class of lipoprotein particles having lipid composition similar to low-density lipoprotein (LDL) and a protein moiety, apoB100, covalently linked to apo(a), a glycoprotein with striking structural similarities to plasminogen. High plasma levels of Lp(a) are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD) by mechanisms yet to be determined. From in vitro and ex vivo observations it is apparent that because of its structural properties, Lp(a) can have both atherogenic and thrombogenic potentials. Means for correcting the high plasma levels of Lp(a) are still limited in effectiveness. The emerging notion that the pathogenicity of Lp(a) is increased in the presence of other risk factors, invites development of approaches for their correction, particularly in subjects with personal and/or family history of ASCVD.

Arteriosclerosis↗
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↗