PubMed Health⌕ Search

Biomedical subjects

V Mooser

Publications and source records attributed to V Mooser.

At least 37 records · Page 2Linked to original sources
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

High plasma levels of apo(a) fragments in Caucasians and African-Americans with end-stage renal disease: implications for plasma Lp(a) assay.

Apolipoprotein(a) [apo(a)] is a plasma glycoprotein that is highly polymorphic in size due to differences in the number of a tandemly arrayed cysteine-rich repeat called kringle (K)4 at its N-terminus. Most plasma apo(a) is covalently attached to apolipoprotein B-100 and circulates as part of lipoprotein(a) [Lp(a)]. A fraction of apo(a) circulates free of lipoproteins. Almost all of the free apo(a) consists of fragments containing variable numbers of K4 repeats derived from the N-terminal region. Previously we provided evidence suggesting that the apo(a) fragments present in human plasma are the source of the apo(a) fragments in human urine. If this were the case, it would be expected that plasma levels of fragments would be higher in subjects with end-stage renal disease (ESRD). In this paper we quantified the levels of apo(a) fragments and plasma Lp(a) in 26 Caucasian and 26 African-American subjects with ESRD and 52 healthy subjects matched for race, sex and the size of the apo(a) isoforms. The plasma levels of apo(a) fragments and Lp(a) were both higher in the ESRD subjects. In addition, the ratio of apo(a) fragments to total immunodetectable apo(a) was increased in ESRD. To determine how much the increase in the apo(a) fragments contributed to the increase in plasma Lp(a) in ESRD, the plasma Lp(a) levels were measured employing two different anti-apo(a) enzyme-linked immunoabsorption assays (ELISA). One assay detected both free and bound apo(a), whereas the other assay detected only bound apo(a). Although the plasma levels of apo(a) in the ESRD subjects tended to be higher using the assay that detected both fragments and full-length apo(a), the increase was modest. Thus, although a greater proportion of the apo(a) in ESRD plasma circulates as fragments, most of the elevation in plasma levels of Lp(a) associated with renal insufficiency is due to an increase in intact Lp(a).

Adolescent↗
PubMed1997

Determinants of plasma platelet-activating factor acetylhydrolase: heritability and relationship to plasma lipoproteins.

Plasma platelet-activating factor acetylhydrolase (PAF-AH) is the enzyme that inactivates PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). We determined the relative contributions of genetic and environmental factors to variation in plasma PAF-AH activity in 240 individuals from 60 nuclear families. Regression of mean-offspring PAF-AH activity on the mid-parent value indicated that 62% of the variation in plasma PAF-AH activity was heritable. Spousal values were weakly negatively correlated, indicating that familial aggregation of PAF-AH activity is due to genetic rather than to environmental factors. Among normolipidemic individuals, plasma PAF-AH activity was strongly correlated with the plasma concentration of low density lipoprotein cholesterol (LDL-C), and treatment with lovastatin resulted in proportional decreases in plasma PAF-AH activity and LDL-C concentrations. To further elucidate the relationship between PAF-AH and plasma concentrations of LDL, plasma PAF-AH activity was measured in families with well-defined, monogenic disorders of LDL metabolism. Plasma PAF-AH activity cosegregated with plasma LDL-C concentrations in familial hypercholesterolemia, but not in familial hypobetalipoproteinemia. We speculate that the rate of removal of LDL from the circulation may determine the clearance rate of PAF-AH, thereby modulating the activity of PAF-AH in blood.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1996

Kringle-containing fragments of apolipoprotein(a) circulate in human plasma and are excreted into the urine.

Apolipoprotein(a) [apo(a)] contains multiple kringle 4 repeats and circulates as part of lipoprotein(a) [Lp(a)]. Apo(a) is synthesized by the liver but its clearance mechanism is unknown. Previously, we showed that kringle 4-containing fragments of apo(a) are present in human urine. To probe their origin, human plasma was examined and a series of apo(a) immunoreactive peptides larger in size than urinary fragments was identified. The concentration of apo(a) fragments in plasma was directly related to the plasma level of Lp(a) and the 24-h urinary excretion of apo(a). Individuals with low (< 2 mg/dl) plasma levels of Lp(a) had proportionally more apo(a) circulating as fragments in their plasma. Similar apo(a) fragments were identified in baboon plasma but not in conditioned media from primary cultures of baboon hepatocytes, suggesting that the apo(a) fragments are generated from circulating apo(a) or Lp(a). When apo(a) fragments purified from human plasma were injected intravenously into mice, a species that does not produce apo(a), apo(a) fragments similar to those found in human urine were readily detected in mouse urine. Thus, we propose that apo(a) fragments in human plasma are derived from circulating apo(a)/Lp(a) and are the source of urinary apo(a).

Animals↗
PubMed1996

Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a).

Apo(a) is a large glycoprotein of unknown function that circulates in plasma as part of lipoprotein(a). Apo(a) is structurally related to plasminogen and contains at least 10 kringle (K)4 repeats (type 1-10), a K5 repeat and sequences similar to the protease domain of plasminogen. Plasminogen generates two biologically active peptides: plasmin and angiostatin, a kringle-containing peptide. As a first step in determining if apo(a) generates a similar kringle-containing peptide, human urine was immunologically examined. Fragments ranging in size from 85 to 215 kD were immunodetected using antibodies directed against epitopes in the K4-type 2 repeat, but not the K4-type 9 repeat or protease domain, NH2-terminal sequence analysis revealed sequences specific for the K4-type 1 repeat, confirming that the fragments are from the NH2 terminus of the K4 array. The amount of urinary apo(a) rose in proportion to the plasma lipoprotein(a) concentration. Even individuals with trace to no apo(a) in plasma had immunodetectable apo(a) fragments in their urine. Intravenous administration of the human urinary apo(a) into mice resulted in the urine. These findings suggest that the apo(a) fragments found in urine are formed extrarenally and then excreted by the kidney.

Amino Acid Sequence↗
PubMed1995

Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma.

Most of the interindividual variations in plasma levels of lipoprotein(a) [Lp(a)] can be attributed to sequence differences linked to the apolipoprotein(a) [apo(a)] locus. Plasma levels of Lp(a) tend to be inversely related to the number of kringle 4 (K4)-encoding sequences in the apo(a) gene, but there are several exceptions to this general trend. Other aspects of the apo(a) gene, in addition to the number of K4 repeats, affect plasma levels of Lp(a). To identify sequences in the apo(a) gene that contribute to plasma Lp(a) levels, we characterized the relationship between a length polymorphism [(TTTTA)n] located 1.3 kb 5' of the first exon of the apo(a) gene, the number of K4 repeats in the gene, and the plasma levels of Lp(a). There was significant linkage disequilibrium between the number of TTTTA repeats and the number of K4 repeats. All of the apo(a) alleles with 11 TTTTA repeats contained fewer than 24 K4 repeats and were paradoxically associated with low plasma Lp(a) levels (< or = mg/dl). To determine whether this association was due to the effect of the 11 TTTTA copies on apo(a) gene transcription, we measured the ability of fragments containing 11 or eight TTTTA repeats to promote transcription when introduced into cultured human hepatocarcinoma cells. No difference was found in the transcriptional activity of the two fragments. The TTTTA repeat constitutes the first sequence polymorphism at the apo(a) locus, other than the number of K4 repeats, which is associated with plasma concentrations of Lp(a).

Alleles↗
PubMed1995

Sequence microheterogeneity in apolipoprotein(a) gene repeats and the relationship to plasma Lp(a) levels.

Lipoprotein(a) [Lp(a)] is a cholesterol ester-rich atherogenic lipoprotein that is composed of a particle of low density lipoprotein and a large glycoprotein, apolipoprotein(a) [apo(a)]. Apolipoprotein(a) varies in size over a approximately 500 kDa range due to inter-allelic differences in the number of tandemly repeated kringle 4 (K4)-encoding 5.5 kb sequences in the apo(a) gene. Only one of the 10 different types of K4 repeats in the apo(a) gene, the so-called type 2 K4 repeats, vary in number between apo(a) alleles. In this paper, we show that there is microheterogeneity within the sequence of the type 2 K4 repeat. DraIII restriction digestion and genomic blotting revealed that a subset of the type 2 K4-encoding sequences contained a DraIII site (K4-D). The proportion of apo(a) alleles that had at least one K4-D repeat ranged from 25% in Caucasians to 50% in the Chinese. K4-D repeats were clustered at the end(s) of the type 2 K4 tandem array and the number and patterns of the K4-D repeats were in linkage disequilibrium with flanking sequence polymorphisms; these features are remarkably similar to the minisatellite variant repeats (MVRs) found in variable number of tandem repeat sequences (VNTRs). In addition, a DraIII pattern that comprised 9% of the sample was invariably associated with low plasma levels of Lp(a) in Caucasians.

Apolipoproteins↗
PubMed1995

Relative contributions of apolipoprotein(a) and apolipoprotein-B to the development of fatty lesions in the proximal aorta of mice.

Transgenic mice expressing transgenes for both human apolipoprotein B-100 (h-apoB) and apolipoprotein(a) [apo(a)] were fed a high-fat, atherogenic diet for 14 weeks to examine the effect of lipoprotein(a) [Lp(a)]on the development of aortic fatty lesions. The extent of lesions in the proximal region of the aorta of Lp(a) mice was measured by use of a computer-assisted image analysis of 20 sections per animal and compared with that of nontransgenic mice as well as mice expressing either the apo(a) or h-apoB transgene. The control (n = 23) and apo(a) (n = 22) transgenic mice had very small mean lesions areas (607 versus 128 microns2 per section). The h-apoB-expressing mice (n = 20) had significantly higher mean lesion areas (3288 microns2 per section) than either the control or apo(a) transgenic animals. Coexpression of apo(a) and h-apoB transgenes resulted in only a modest increase in lesion area (4678 microns2 per section, n = 19). Thus, the expression of human apo(a) in C57BL/6/SJL hybrid mice fed an atherogenic diet failed to significantly potentiate the development of aortic fatty lesions in the absence or presence of high levels of h-apoB.

Animals↗
PubMed1994

[Paradoxical pulse].

Pulsus paradoxus is one of the cardinal signs of cardiac tamponade and must be looked for at bedside examination of any patient who presents a clinical picture of low cardiac output. This paper reviews the definition of pulsus paradoxus and the way to measure it noninvasively. We then discuss the physiological fluctuation of systemic blood pressure during respiration and the various mechanisms which lead to an exaggeration of this phenomenon during tamponade. The sensitivity and specificity of this sign are also discussed. Finally, the role of echocardiography in the diagnosis of cardiac tamponade is shortly presented, as this method appears to be very accurate and sensitive in evaluating the hemodynamic embarrassment associated with pericardial effusion.

Blood Pressure↗
PubMed1993

Monoclonal antibodies to arginine vasopressin receptor bind to liver, kidney and pituitary membranes.

1. A vasopressin binding protein purified from rat liver membranes was used to immunize Balb/c mice and, subsequently, for the screening of hybrids raised in two different cell fusions. 2. Three hybrids were obtained which secreted monoclonal antibodies (MoAb) that bound to the purified solubilized receptor as detected by an enzyme-linked immunosorbent assay technique. All three MoAb immunoprecipitated the purified receptor. 3. In addition, the MoAb bound in a concentration-dependent manner to crude liver, kidney and anterior pituitary membranes, tissues known to contain arginine vasopressin (AVP) receptors but not to cardiac ventricle membranes which lack AVP receptors. 4. However, the binding of [125I]-[d(CH2)5,Sar7]AVP (a specific radiolabelled V1 antagonist) to the membrane-bound receptor was not inhibited by these antibodies. 5. These results suggest that MoAb recognize epitopes which are common to rat liver, kidney and anterior pituitary membranes but are not at the ligand binding site.

Animals↗
PubMed1992

[Hyperkalemia during prolonged use of angiotensin II-converting enzyme inhibitors in end-stage renal insufficiency].

Hyperkalemia is a severe complication of end-stage renal failure. To evaluate whether ACE inhibitors may even worsen the propensity to develop hyperkalemia in this condition, we have analyzed retrospectively pre-dialytic blood pressure and serum potassium in 15 patients on chronic hemodialysis before and during long-term ACE inhibition. This treatment induced a significant drop in blood pressure (from 173 +/- 3/90 +/- 2 to 159 +/- 5/85 +/- 2 mm Hg [p < 0.05]), whereas serum potassium increased from 4.9 +/- 0.2 to 5.5 +/- 0.2 mM (p < 0.05), irrespective of the dosage of ACE inhibitor and of the residual diuresis. Hyperkalemia was well tolerated and was corrected in all patients by dialysis; treatment was discontinued in only one case. In conclusion, ACE inhibitors represent effective antihypertensive treatment in end-stage renal failure. However, long-term ACE inhibition may be accompanied by a worsening of hyperkalemia, which could be accounted for by a reduced effect of aldosterone on extrarenal potassium homeostasis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Isolation and characterization of the rat liver AVP receptor using [125I][d(CH2)5'sarcosine7]AVP.

1. A vasopressin (AVP) binding protein was purified from rat liver membranes by an improved method using [125I][d(CH2)5'Sarcosine7]AVP, a selective V1 AVP radioligand and a combination of CHAPS solubilization, gel filtration, lectin affinity and FPLC ion exchange chromatography. 2. The purified protein exhibited a maximum binding activity of 2480 pmol/mg protein with a KD of 4.5 nmol/L, which corresponds to a purification of approximately 26,700-fold. The molecular weight of this protein was 70,000 Da. 3. The binding of [125I][d(CH2)5'Sarcosine7]AVP to the solubilized membranes was dependent on the protein concentration, and was inhibited by the unlabelled peptides [d(CH2)5'Sarcosine7]AVP, AVP, and to a lesser degree by peptides with high V2 receptor affinity, such as 1-desamino-D-AVP and [d(CH2)5'D-Ileu2-Ileu4]AVP. 4. In addition, an AVP anti-idiotypic monoclonal antibody bound to both the partially purified and purified lectin affinity AVP binding protein in a concentration-dependent manner. These results indicate that the purified protein displays similar characteristics to the liver membrane-bound AVP V1 receptor.

Animals↗
PubMed1992

Conduit artery compliance and distensibility are not necessarily reduced in hypertension.

The goal of this study was to investigate whether the elastic behavior of conduit arteries of humans or rats is altered as a result of concomitant hypertension. Forearm arterial cross-sectional compliance-pressure curves were determined noninvasively by means of a high precision ultrasonic echo-tracking device coupled to a photoplethysmograph (Finapres system) allowing simultaneous arterial diameter and finger blood pressure monitoring. Seventeen newly diagnosed hypertensive patients with a humeral blood pressure of 163/103 +/- 4.4/2.2 mm Hg (mean +/- SEM) and 17 age- and sex-matched normotensive controls with a humeral blood pressure of 121/77 +/- 3.2/1.9 mm Hg were included in the study. Compliance-pressure curves were also established at the carotid artery of 16-week-old anesthetized spontaneously hypertensive rats (n = 14) as well as Wistar-Kyoto normotensive animals (n = 15) using the same echo-tracking device. In these animals, intra-arterial pressure was monitored in the contralateral carotid artery. Mean blood pressures averaged 197 +/- 4 and 140 +/- 3 mm Hg in the hypertensive and normotensive rats, respectively. Despite the considerable differences in blood pressure, the diameter-pressure and cross-sectional compliance-pressure and distensibility-pressure curves were not different when hypertensive patients or animals were compared with their respective controls. These results suggest that the elastic behavior of a medium size muscular artery (radial) in humans and of an elastic artery (carotid) in rats is not necessarily altered by an increase in blood pressure.

Animals↗
PubMed1991

Changes in cardiac angiotensin converting enzyme after myocardial infarction and hypertrophy in rats.

1. Cardiac angiotensin-converting enzyme (ACE) is localized in high concentration in cardiac valves, coronary vessels, right and left atrium and right and left ventricle. 2. Cardiac ACE is functionally active in converting angiotension I to angiotensin II. 3. The level of cardiac ACE measured by radioinhibitor binding or by quantitative in vitro autoradiography was greatly increased after experimental myocardial infarction in the rat. The increase was greatest in the fibrous scar tissue of the free left ventricular wall infarct, but there were also significant increases in the ACE concentration in the four chambers of the heart. 4. Treatment with enalapril for 4 weeks following coronary ligation inhibited cardiac ACE, including the high levels found in the scar in the left ventricular free wall. 5. There was a close relationship between the systolic blood pressure and left ventricular mass in several models of experimental hypertension, despite varying degrees of activation of the renin-angiotensin system. However no relationship between the degree of left ventricular hypertrophy and changes in cardiac ACE could be determined. 6. Inhibition of cardiac ACE may contribute to the beneficial effect of ACE inhibitors in cardiac hypertrophy and remodelling, and may play a part in the cardioprotective role of ACE inhibitor.

Animals↗
PubMed1991

Reduction in left ventricular mass in normotensive and spontaneously hypertensive rats given enalapril.

1. To test the hypothesis that the reduction of left ventricular weight (LVW) observed during angiotensin-converting enzyme (ACE) inhibition in rats is mainly a response to decreased cardiac load, the effect of enalapril on LVW and blood pressure (BP) in normotensive Sprague-Dawley (SD) and in spontaneously hypertensive rats (SHR) was compared. 2. Enalapril decreased BP by 10% in SD rats and 21% in SHR; and LVW by 6% in SD rats and 12% in SHR. A close linear correlation between BP and LVW was observed in SD (r = 0.65, n = 24, P less than 0.001) and SHR (r = 0.92, n = 15, P less than 0.001). 3. The effect of enalapril on LVW, when related to BP, was almost identical in SD and SHR, as the average reduction of LVW (microgram/g of bodyweight) per mmHg was 7.7 +/- 1.9 versus 7.5 +/- 0.9 in SD and SHR respectively. 4. These data constitute additional evidence to support the view that, at least under ACE inhibition, reduction in LVW is mainly due to the fall in BP and the decreased cardiac load.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Characterization of monoclonal antibodies to a rat liver vasopressin receptor.

1. Balb/c mice were immunized against a vasopressin binding protein purified from rat liver. The hybrids produced from two cell fusions were screened against this receptor. Three hybrids were selected, cloned and expanded in serum-free media. The monoclonal antibodies (MoAb) secreted by these three hybrids were of the subclass IgM and were able to immunoprecipitate [125I]-labelled purified receptor. 2. All three MoAb bound to the purified solubilized receptor, crude liver and kidney membranes in a concentration-dependent manner. However, the binding of MoAb to the membranes did not inhibit the binding of [125I]-[d(CH2)5,Sar7]AVP, a selective V1 receptor radioligand, to the liver membrane-bound receptor. 3. These results suggest that the three MoAb recognize epitopes on the V1 receptor which are not denatured by solubilization, but are common to both rat liver and kidney membranes.

Animals↗