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Biomedical subjects

S M Marcovina

Publications and source records attributed to S M Marcovina.

At least 19 recordsLinked to original sources
PubMed1999

Relationship between phospholipid transfer protein activity and HDL level and size among inbred mouse strains.

Because of the paucity of data on phospholipid transfer protein (PLTP) activity and lipoprotein phospholipid in mouse strains, plasma PLTP activity (PLTA), plasma phospholipid and cholesterol, HDL phospholipid and cholesterol, and HDL size distribution were determined in 15 inbred mouse strains. The 15 inbred mouse strains differed in their relatedness to one another and consisted of six largely unrelated groups: Castaneus, Swiss, C57BL, AKR, DBA, and NZB. Lipid and PLTA analyses were performed on plasma pools from male and female mice that had fasted for 4 h prior to blood draw. Among the representative unrelated strains fed the chow diet, there was a highly significant relationship between PLTA and plasma phospholipid (r(s) = 0.727, P < 0.01), HDL phospholipid (r(s) = 0.762, P < 0.01), HDL cholesterol (r(s) = 0.699, P < 0.02), percentage of large HDL particles (r(s) = 0.699, P < 0.02), and HDL peak size (r(s) = 0.776, P < 0.01). Similar results were obtained among these strains fed a high fat, high cholesterol diet. PLTA increased in all strains fed the high fat diet (chix = 94%, range 6 to 221%). Strain SM having relatively low PLTA and HDL was crossed with strain NZB having high PLTA and HDL. The F1 progeny from this cross were backcrossed to strain SM and 41 male backcross progeny collected. Among these individual backcrossed animals, PLTA was highly correlated with plasma phospholipid (r(s) = 0.508, P = 0.001), HDL phospholipid (r(s) = 0.566, P < 0.001), HDL cholesterol (r(s) = 0.532, P < 0.001), and percentage of large HDL particles (r(s) = 0.446, P = 0.020). Therefore, we conclude that PLTP is a determinant of HDL level and size in mice.-Albers, J. J., W. Pitman, G. Wolfbauer, M. C. Cheung, H. Kennedy, A-Y. Tu, S. M. Marcovina, and B. Paigen. Relationship between phospholipid transfer protein activity and HDL level and size among inbred mouse strains.

Animals↗
PubMed1998

Lipoprotein(a) as a risk factor for coronary artery disease.

Since its identification by Kåre Berg in 1963, lipoprotein(a) [Lp(a)] has become a focus of research interest owing to the results of case-control and prospective studies linking elevated plasma levels of this lipoprotein with the development of coronary artery disease. Lp(a) contains a low-density lipoprotein (LDL)-like moiety, in which the apolipoprotein B-100 component is covalently linked to the unique glycoprotein apolipoprotein(a) [apo(a)]. Apo(a) is composed of repeated loop-shaped units called kringles, the sequences of which are highly similar to a kringle motif present in the fibrinolytic proenzyme plasminogen. Variability in the number of repeated kringle units in the apo(a) molecule gives rise to different-sized Lp(a) isoforms in the population. Based on the similarity of Lp(a) to both LDL and plasminogen, it has been hypothesized that the function of this unique lipoprotein may represent a link between the fields of atherosclerosis and thrombosis. However, determination of the function of Lp(a) in vivo remains elusive. Although Lp(a) has been shown to accumulate in atherosclerotic lesions, its contribution to the development of atheromas is unclear. This uncertainty is related in part to the structural complexity of the apo(a) component of Lp(a) (particularly apo(a) isoform size heterogeneity), which also poses a challenge for standardization of the measurement of Lp(a) in plasma. The fact that plasma Lp(a) levels are largely genetically determined and vary widely among different ethnic groups adds scientific interest to the ongoing study of this enigmatic particle. Most recently, the identification of proteolytic fragments of apo(a) in both plasma and urine has fueled speculation about the origin of these fragments and their possible function in the atherosclerotic process.

Coronary Disease↗
PubMed1998

Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial.

CONTEXT: Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment. OBJECTIVE: To determine the effect of this weight gain on lipid levels and blood pressure. DESIGN: Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT). SETTING: Twenty-one clinical centers. PARTICIPANTS: The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline. INTERVENTION: Randomized to receive either intensive (n = 586) or conventional (n = 582) diabetes treatment with a mean follow-up of 6.1 years. MAIN OUTCOME MEASURES: Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain. RESULTS: With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure. CONCLUSIONS: The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time.

Adult↗
PubMed1998

Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions.

BACKGROUND: Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy. METHODS AND RESULT: The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use. CONCLUSIONS: Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.

Aged↗
PubMed1998

Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation.

OBJECTIVES: The purpose of this study was the investigation of the in vivo role of lipoprotein(a) [Lp(a)] and inflammatory infiltrates in the human coronary atherosclerotic plaque and their correlation with the clinical syndrome of presentation. BACKGROUND: Lipoprotein(a) is an atherogenic and thrombogenic lipoprotein, and has been implicated in the pathogenesis of acute coronary syndromes. Lipoprotein(a) induces monocyte chemoattraction and smooth muscle cell activation in vitro. Macrophage infiltration is considered one of the mechanisms of plaque rupture. METHODS: This study of atherectomy specimens investigated the in vivo role of Lp(a) at different stages of the atherogenic process, and its relationship with macrophage infiltration. We examined coronary atheroma removed from 72 patients with stable or unstable angina. Specimens were stained with antibodies specific for Lp(a), macrophages (KP-1), and smooth muscle cells (alpha-actin). Morphometric analysis was used to quantify the plaque areas occupied by each of the three antigens, and their colocalization. RESULTS: All specimens had localized Lp(a) staining; the mean fractional area was 58.2%. Ninety percent of the macrophage areas colocalized with Lp(a) positive areas, whereas 31.3% of the smooth muscle cell areas colocalized with Lp(a) positive areas. Patients with unstable angina (n = 46) had specimens with larger mean plaque Lp(a) areas than specimens from stable angina patients (n = 26): 64.4% versus 47.7% (p = 0.004). Unstable angina patients with rest pain (n = 28) had greater mean plaque Lp(a) area than unstable angina patients with crescendo exertional pain (n = 18): 71.1% versus 52.4% (p < 0.001). Mean KP-1 area was 31.2% in unstable rest angina versus 18.3% in stable angina (p = 0.05); alpha-actin area was greater in stable (48.5%) and crescendo exertional angina (48.8%) than in rest angina (30.4%). The strongest correlation between plaque KP-1 and Lp(a) area was in unstable rest angina (r = 0.88, p < 0.001), and between alpha-actin and Lp(a) areas in the crescendo exertional angina (r = 0.62, p < 0.01). CONCLUSIONS: Lipoprotein(a) is ubiquitous in human coronary atheroma. It is detected in larger amounts in tissue from culprit lesions in patients with unstable compared to stable syndromes, and has significant colocalization with plaque macrophages. A correlation of plaque alpha-actin and Lp(a) area suggests a role of Lp(a) in plaque growth.

Angina Pectoris↗
PubMed1998

Expression of apolipoprotein(a) kringle IV type 9 in Escherichia coli: demonstration of a specific interaction between kringle IV type 9 and apolipoproteinB-100.

A number of studies have provided evidence that lipoprotein(a) [Lp(a)] assembly is a two-step process in which initial non-covalent interactions between apolipoprotein(a) [apo(a)] and apolipoproteinB-100 (apoB-100) precede specific disulfide bond formation. We have designed a construct encoding apo(a) kringle IV type 9 (KIV9) in which the unpaired cysteine at position 67 in this kringle is replaced with a tyrosine. The single kringle was expressed in bacteria and purified to homogeneity from cell homogenates. The purified derivative (designated KIV9deltaCys) was assessed for its ability to bind to purified human LDL. This interaction was detected either by ELISA using immobilized LDL or by column chromatography in which LDL binding to KIV9deltaCys immobilized on Ni2+-Sepharose was determined. In both cases, the interaction of KIV9deltaCys and LDL was observed. Further, we demonstrated that the binding interaction was sensitive to the addition of amino acids including lysine, the lysine analogue epsilon-aminocaproic acid, arginine, phenylalanine and proline, with arginine and lysine having the greatest inhibitory effect. Binding of KIV9deltaCys to an immobilized apoB peptide spanning residues 3732-3745 of apoB was also demonstrated by ELISA. As was the case for LDL, this binding interaction was sensitive to the addition of arginine and lysine. Computer modeling of KIV9 demonstrated an excellent fit with residues 3732-3738 (PSCKLDF) of the apoB peptide. The modeling predicts the presence of overlapping lysine and phenylalanine-binding pockets in KIV9 which explains the inhibitory effects of lysine, arginine and phenylalanine which were observed in the binding assays. In summary, this study represents the first demonstration that KIV9 can interact directly with LDL through non-covalent interactions which may contribute to the first step of Lp(a) formation.

Amino Acid Sequence↗
PubMed1998

Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide SFLLRN.

Elevated levels of lipoprotein(a) [Lp(a)] are correlated with an increased risk of atherosclerotic disease. We examined the effect of recombinant apolipoprotein(a) [r-apo(a)] and Lp(a) on responses of washed human platelets, prelabeled in the dense granules with [14C]serotonin and suspended in Tyrode's solution, to ADP and the thrombin receptor-activating peptide SFLLRN. No effect of the 17 kringle (K), 12K, or 6K r-apo(a) derivatives (at concentrations of 0.35 and 0.7 micromol/L) or Lp(a) (up to 0.1 micromol/L) on primary ADP-induced platelet aggregation was observed. In contrast, weak platelet responses stimulated by 7.5 micromol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 micromol/L 17K r-apo(a) increased aggregation from 15+/-4% to 58+/-6%, release of [14C]serotonin from 9+/-3% to 36+/-6%, and formation of thromboxane A2, measured as its stable metabolite thromboxane B2, from 7+/-1 to 29+/-5 ng/10(9) platelets (n=3; P<0.04 to 0.015). Significant enhancement of aggregation and release of granule contents was observed at a concentration of 17K r-apo(a) as low as 0.175 micromol/L. Purified Lp(a) (0.25 to 0.1 micromol/L) also enhanced SFLLRN-induced aggregation and release in a dose-dependent manner. Although plasminogen (0.7 and 1.5 micromol/L) and low density lipoprotein (0.025 to 0.1 micromol/L) both exhibited potentiating effects on SFLLRN-mediated platelet aggregation, the magnitude of the responses was less than that observed with either the r-apo(a) derivatives or Lp(a). The enhanced responses of platelets via the protease-activated receptor- thrombin receptor in the presence of Lp(a) may contribute to the increased risk of thromboembolic complications of atherosclerosis associated with this lipoprotein.

Adenosine Diphosphate↗
PubMed1998

Plasma apolipoproteins A-I and B in survivors of myocardial infarction and in a control group.

The values of apolipoproteins (apo) A-I and B were determined in a population sample of hospital outpatients with a standardized method to verify if the cutpoints calculated in a cross-sectional study in the US are usable with other populations. We also tested the apolipoproteins' ability to discriminate between healthy people and survivors of myocardial infarction. In the studied population the apo A-I value corresponding to the HDL-cholesterol decisional centile is 1.12 g/L for males and 1.17 g/L for females; the apo B value corresponding to the LDL-cholesterol decisional centile is 1.23 g/L for males and 1.14 g/L for females. These values are quite close to the cutpoints proposed for the American population (1.20 g/L for both apolipoproteins). In comparison with the LDL- and HDL-cholesterol decisional concentrations, the cutpoints for apolipoproteins allow a correct classification of a greater percentage of postmyocardial infarction patients (16% higher for apo B and 5% for apo A-I). Standardized assays coupled with a reference database allow a better clinical use of apolipoprotein measurements.

Adult↗
PubMed1998

Apolipoprotein B and A-I values in 147576 Swedish males and females, standardized according to the World Health Organization-International Federation of Clinical Chemistry First International Reference Materials.

Serum concentrations of apolipoprotein (apo) B and apo A-I were measured from 1985-1996 in a Swedish population sample of 83 112 males and 64 464 females, ages <20 to >80 years, using an automated immunoturbidimetric method calibrated against fresh pools of human serum and commercial calibrators. All values were recalculated in 1997 after calibration against the WHO-IFCC First International Reference Materials. The recalculation factor was 1.059 for apo B, whereas for apo A-I, the correction was: y = 0.989x + 0.101. The total CVs for both apo B and A-I were generally <7%. The mean value (+/- SD) for apo B was 1.31 +/- 0.35 g/L in all males and 1.22 +/- 0.36 g/L in all females. The mean apo A-I concentration was 1.36 +/- 0.22 g/L in males-10% lower than in females (1.51 +/- 0.24 g/L). The mean value of apo B increased up to 60 years of age in males and up to 70 years of age in females. apo A-I concentrations changed only slightly with age in both males and females. apo A-I concentrations among Swedes are nearly identical to those reported recently by two American studies and those obtained in a Finnish population sample. Mean apo B concentrations differ somewhat between the populations but mirror-as expected-differences in total cholesterol concentrations. The highest values were noted in Swedish subjects. The Swedish sample population is, to our knowledge, the largest describing the distribution of apo B and A-I in a general population of adult males and females of all ages determined with procedures standardized and traceable to the WHO-IFCC First International Reference Materials.

Adult↗
PubMed1998

Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure-function relationships and studies in a compound heterozygous proband.

Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency. Exon sequence determination of the LCAT gene of the proband revealed two novel heterozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino acid substitutions (Thr13Met and Pro307Ser, respectively). To assess the distinct functional impact of the separate mutant alleles, studies were conducted in the proband's 3-generation pedigree. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband's mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. The proband's father and two daughters were heterozygous for the Thr13Met mutation and also displayed low HDL, reduced LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely impaired in the compound heterozygous proband and was reduced by 50% in individuals heterozygous for either mutation, compared to wild type family members. It is also shown that the two mutations impair both catalytic activity and expression of the circulating protein.

Adult↗
PubMed1997

Transgenic mice expressing human ApoB95 and ApoB97. Evidence that sequences within the carboxyl-terminal portion of human apoB100 are important for the assembly of lipoprotein.

The structural features of apolipoprotein (apo) B that are important for its covalent linkage to apo(a) to form lipoprotein(a) (Lp(a)) are incompletely understood. Although apoB100 cysteine 4326 is required for the disulfide linkage with apo(a), other structural features, aside from a single free cysteine residue, must be important for apoB's initial interaction with apo(a) and for facilitating the formation of the disulfide bond. To determine if sequences carboxyl-terminal to cysteine 4326 affect the efficiency of Lp(a) formation, we used "pop-in, pop-out" gene targeting in a human apoB yeast artificial chromosome to introduce nonsense mutations into exon 29 of the apoB gene. The mutant yeast artificial chromosomes, which coded for the truncated versions of human apoB, apoB95, and apoB97, were then used to express these mutant forms of apoB in transgenic mice. As judged by in vitro assays of Lp(a) formation, apoB95 (4330 amino acids) formed a small amount of Lp(a) but did so slowly. In contrast, apoB97 (4397 amino acids) formed Lp(a) rapidly, although not quite as rapidly as the full-length apoB100 (4536 amino acids). These results were supported by an analysis of double-transgenic mice expressing both human apo(a) and either apoB95 or apoB97. In mice expressing both apoB95 and apo(a), there was only a trace amount of Lp(a) in the plasma, and most of the apo(a) was free, whereas in mice expressing both apoB97 and apo(a), virtually all of the apo(a) was bound to apoB97 in the form of Lp(a). These results show that sequences carboxyl-terminal to apoB95 (amino acids 4331-4536) are not absolutely required for Lp(a) formation, but this segment of the apoB molecule, particularly residues 4331-4397, is necessary for the efficient assembly of Lp(a).

Animals↗
PubMed1997

The solution phase interaction between apolipoprotein(a) and plasminogen inhibits the binding of plasminogen to a plasmin-modified fibrinogen surface.

In the present study, we assessed the binding of recombinant forms of apolipoprotein(a) [r-apo(a)] to plasminogen. Apo(a)-plasminogen interactions were demonstrated to be lysine-dependent, as they were abolished by the addition of epsilon-aminocaproic acid. Binding of r-apo(a) and plasma-derived Lp(a) to Glu-plasminogen was assessed in solution using a mutant form of recombinant plasminogen [Plg(S741C)] labeled at the active site with 5'-(iodoacetamido)fluorescein. High-affinity binding of apo(a) to plasminogen was observed with the 17-kringle r-apo(a) (Kd = 20.1 +/- 3.3 nM) as well as with plasma-derived Lp(a) (Kd = 5.58 +/- 0.08 nM). Binding studies using various truncated and mutant forms of r-apo(a) demonstrated that sequences within apo(a) kringle IV types 2-9 and the strong lysine binding site (LBS) in apo(a) kringle IV type 10 are not required for high-affinity binding to plasminogen. In all cases, the binding stoichiometry for the apo(a)-plasminogen interaction was determined to be 1:1. Binding data obtained using a 17-kringle r-apo(a) derivative lacking the protease-like domain (17KDeltaP; Kd = 3158 +/- 138 nM) indicate that sequences within the protease-like domain of apo(a) mediate its interaction with LBS in plasminogen. We determined that r-apo(a) and plasminogen bind to distinct sites on plasmin-modified fibrinogen with the concentration of plasminogen binding sites exceeding the concentration of r-apo(a) sites by a factor of 10. Furthermore, r-apo(a) is capable of inhibiting the binding of plasminogen to plasmin-modified fibrinogen surfaces, an effect which we show is attributable to the formation of a solution phase apo(a)/plasminogen complex which exhibits a greatly reduced affinity for plasminogen binding sites on plasmin-modified fibrinogen. The results of this study provide new insights into the mechanism by which apo(a) and Lp(a) may inhibit fibrinolysis, thus contributing to the atherothrombotic risk associated with this lipoprotein.

Aminocaproic Acid↗
PubMed1997

Serum distribution of lipoprotein(a) in African Americans and Nigerians: potential evidence for a genotype-environmental effect.

Differences in lipoprotein(a) [Lp(a)] levels across populations have been described and blacks are known to have higher Lp(a) values compared to whites. However, environmental factors which influence Lp(a) levels have been difficult to identify. We took advantage of the large environmental contrast which exists against a common genetic background between U.S. and Nigerian blacks to examine the relationship between Lp(a) and apolipoprotein(a) magnitude of apo(a) isoforms. Although the distribution of Lp(a) and apo(a) isoforms was nearly Gaussian in both populations, mean serum Lp(a) values were significantly higher in the United States than in Nigeria (20.5 vs. 12.7 mg/dl; P = 0.0001) and U.S. blacks had a higher frequency of the large molecular weight isoforms compared to Nigerians. Similar trends in the relationship between apo(a) isoform and Lp(a) concentration were seen in both populations; however, the magnitude of the effect was different. Compared to the Nigerians, U.S. blacks had significantly higher mean Lp(a) values for the same apo(a) isoform. The association of Lp(a) with low density lipoprotein-cholesterol (LDL-C) level was not significant after correcting for the contribution of Lp(a) cholesterol to LDL-C in both populations. Surprisingly, the association between Lp(a) and total-C remained significant (r = 0.20, P = 0.04) after similar correction for the contribution of Lp(a) cholesterol in the U.S. sample. Understanding the relationship between other factors including lifestyle characteristics capable of influencing total-C may help explain the unusually high Lp(a) level observed in this U.S. population.

Adult↗
PubMed1997

Lipoprotein(a): structural implications for pathophysiology.

The assembly between a low-density lipoprotein particle and apolipoprotein(a), a highly carbohydrate-rich protein, gives origin to a peculiar class of lipoproteins, only found in the hedgehog, primates, and humans, termed lipoprotein(a). Apolipoprotein(a), which shares a high degree of sequence homology with the fibrinolytic proenzyme plasminogen, is linked to the apolipoprotein B-100 component of low-density lipoprotein via a disulfide bond and confers distinct biochemical and metabolic properties to lipoprotein(a). Because of its peculiar structural features and the observed correlation between high lipoprotein(a) levels and the development of a variety of atherosclerotic disorders, this lipoprotein has become the focus of an intense research effort. Although accumulation of lipoprotein(a) in the vessel wall at sites of vascular injury has been clearly evidenced, the mechanism(s) by which lipoprotein(a) exerts its pathogenic effect in this milieu remain largely unknown. It has been hypothesized that the pathological effect of lipoprotein(a) is related either to its similarity to low-density lipoprotein (i.e., a pro-atherogenic effect) or to the apolipoprotein(a) similarity to plasminogen (i.e., a pro-thrombotic/anti-fibrinolytic effect). However, it is probable that both components contribute to the pathogenicity of lipoprotein(a). The fact that lipoprotein(a) levels are largely genetically determined, varying widely among individuals and racial groups, adds additional elements to the scientific interest that surrounds this lipoprotein. Both clinical and biochemical studies of lipoprotein(a) have been complicated by the high degree of structural heterogeneity of apolipoprotein(a), which is considered the most polymorphic protein in human plasma. Our aim in this paper is to provide an overview of the most salient structural features of lipoprotein(a) and their possible pathophysiological implications.

Apolipoproteins A↗
PubMed1997

The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans.

The distributions of plasma lipoprotein(a), or Lp(a), levels differ significantly among ethnic groups. Individuals of African descent have a two- to threefold higher mean plasma level of Lp(a) than either Caucasians or Orientals. In Caucasians, variation in the plasma Lp(a) levels has been shown to be largely determined by sequence differences at the apo(a) locus, but little is known about either the genetic architecture of plasma Lp(a) levels in Africans or why they have higher levels of plasma Lp(a). In this paper we analyze the plasma Lp(a) levels of 257 sibling pairs from 49 independent African American families. The plasma Lp(a) levels were much more similar in the sibling pairs who inherited both apo(a) alleles identical by descent (IBD) (r = .85) than in those that shared one (r = .48) or no (r = .22) parental apo(a) alleles in common. On the basis of these findings, it was estimated that 78% of the variation in plasma Lp(a) levels in African Americans is attributable to polymorphism at either the apo(a) locus or sequences closely linked to it. Thus, the apo(a) locus is the major determinant of variation in plasma Lp(a) levels in African Americans, as well as in Caucasians. No molecular evidence was found for a common "high-expressing" apo(a) allele in the African Americans. We propose that the higher plasma levels of Lp(a) in Africans are likely due to a yet-to-be-identified trans-acting factor(s) that causes an increase in the rate of secretion of apo(a) or a decrease in its catabolism.

Adolescent↗
PubMed1997

Biological and lifestyle factors, and lipid and lipoprotein levels among Japanese Americans in Seattle and Japanese men in Japan.

BACKGROUND: It has been previously shown that Japanese Americans in Seattle have significantly higher cholesterol levels than native Japanese. The present study examines the association of biological and lifestyle factors with plasma lipid and lipoprotein levels among Japanese Americans (JA) and native Japanese (NJ) to determine if these associations are consistent between these high and low cholesterol populations. METHODS: Study samples consisted of 710 JA male and 728 JA female volunteers living in the Seattle area and a random sample of 3833 NJ male urban workers who participated in parallel cardiovascular disease screening and lifestyle surveys for 1989-1994. Multiple regression analysis was conducted to examine the association of lifestyle and biological factors with lipid and lipoprotein levels. RESULTS: Alcohol consumption was positively and linearly associated with high density lipoprotein cholesterol (HDL-C) levels and negatively associated with both low density lipoprotein cholesterol (LDL-C) levels and the ratio of total cholesterol (TC)/HDL-C (P < 0.05 to P < 0.001) among JA males and JA females and NJ males. Current smoking habit was observed to be negatively associated with HDL-C levels and positively with TC/HDL-C ratio and log TG levels (logarithmic transformation of triglyceride values) (P < 0.05 to P < 0.001) among all three groups. Body mass index (BMI) was negatively associated with HDL-C levels and positively associated with log TG and TC/HDL-C ratio among all three groups (P < 0.05 to P < 0.001). Moderate alcohol consumption was negatively associated with log TG levels among JA males and females (P < 0.05), whereas heavy alcohol consumption was positively associated with log TG levels in NJ males (P < 0.001). Smoking was positively associated with TC and LDL-C levels (P < 0.05) among JA males, whereas a negative association (P < 0.05) was observed in NJ males. CONCLUSION: Overall, the fitted models were consistent between JA males and females and NJ males with the exception of smoking on TC and LDL-C. The results suggest that moderate alcohol consumption favourably influences lipid profiles in both high and low cholesterol populations. The results also indicate that light alcohol consumption is associated with decreased triglyceride levels, whereas heavy alcohol consumption is associated with increased triglyceride levels.

Adult↗
PubMed1997

Analysis of the mechanism of lipoprotein(a) assembly.

We have assessed the ability of a battery of purified recombinant apolipoprotein(a) (r-apo(a)) derivatives to bind to immobilized low-density lipoprotein (LDL) by ELISA. Removal of the apo(a) kringle IV type 8 and type 9 sequences dramatically reduced apo(a) binding to LDL. The binding of apo(a) to LDL was effectively inhibited by arginine, lysine, the lysine analogue epsilon-aminocaproic acid and proline; comparable inhibition was observed using the 17K and KIV5-8 r-apo(a) derivatives, suggesting a direct role for sequences contained in the latter species in mediating the initial non-covalent interactions which precede specific disulfide bond formation. We also determined that r-apo(a) binds directly to a synthetic apoB peptide spanning amino acid residues 3732-3745; this interaction appeared to be mediated by sequences present in apo(a) kringle IV types 8 and 9, and could be inhibited by arginine, lysine and proline. The results of this study indicate that the efficiency of Lp(a) assembly is a direct function of the initial non-covalent interactions between apo(a) and LDL; in addition, these studies suggest that Cys3734 in apoB mediates covalent linkage with apo(a) by virtue of the ability of the apoB sequences surrounding this residue to directly interact with apo(a) KIV type 9.

Apolipoproteins A↗