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Biomedical subjects

G Luc

Publications and source records attributed to G Luc.

At least 19 recordsLinked to original sources
PubMed1992

Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction.

Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction contribute to the development of coronary heart disease. In a study comparing patients after myocardial infarction with controls, we have explored a possible association between coronary heart disease and a variation found in the gene encoding angiotensin-converting enzyme (ACE). The polymorphism ACE/ID is strongly associated with the level of circulating enzyme. This enzyme plays a key role in the production of angiotensin II and in the catabolism of bradykinin, two peptides involved in the modulation of vascular tone and in the proliferation of smooth muscle cells. Here we report that the DD genotype, which is associated with higher levels of circulating ACE than the ID and II genotypes, is significantly more frequent in patients with myocardial infarction (n = 610) than in controls (n = 733) (P = 0.007), especially among subjects with low body-mass index and low plasma levels of ApoB (P < 0.0001). The ACE/ID polymorphism seems to be a potent risk factor of coronary heart disease in subjects formerly considered to be at low risk according to common criteria.

Adult↗
PubMed1992

A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition.

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .01). Simvastatin increased Lp A-I, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-I and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.

Adolescent↗
PubMed1992

A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease. The ECTIM Study.

The incidence of coronary heart disease (CHD) in middle-aged men is more than three times higher in Northern Ireland than in France. The ECTIM study, which is based on WHO MONICA centers in Belfast (Northern Ireland), Strasbourg (eastern France), Toulouse (southwestern France), and Lille (northern France), has been established to investigate this striking difference. Male patients aged 25-64 years with myocardial infarction (MI) and control subjects sampled from the general population were recruited in the four centers. Hypolipidemic drug treatment was much more frequent in France than in Belfast. "Hypercholesterolemia" defined by the presence of hypolipidemic drug treatment or a low density liproprotein cholesterol level greater than 200 mg/dl was more frequent in cases than in controls in both countries but was similar in both control groups. An in-depth study of lipid variables, including measurements of cholesterol fractions, triglycerides, apolipoproteins (apo), and lipoprotein particles (Lp), was performed in nonhypercholesterolemic subjects. In Northern Ireland and France, patients in comparison with controls had lower levels of high density lipoprotein cholesterol, apo A-I, apo A-II, Lp A-I, and Lp A-II:A-I and higher levels of Lp E:B and Lp(a):B. The levels of triglycerides, very low density lipoprotein cholesterol, apo B, and Lp C-III:B were higher in cases than in controls only in Belfast. In control subjects, the mean levels of cholesterol fractions and apolipoproteins were similar in Northern Ireland and France; however, the level of Lp A-I was lower and the levels of Lp E:B and Lp(a):B were higher in Northern Ireland than in France.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Lipoprotein particle analysis comparing simvastatin and fenofibrate.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.

Adolescent↗
PubMed1991

High-density lipoprotein particles in octogenarians.

High-density lipoprotein (HDL) particles exhibit considerable heterogeneity, specifically in apolipoprotein (apo) composition. Thus, apo A-I, the major protein of HDL, is present in two types of particles: one species contains both apo A-I and apo A-II (Lp A-I/A-II) while in the other (Lp A-I), apo A-II is absent. We used the hypothesis that octogenarians, who survived periods in life when the incidence of coronary heart disease (CHD) is very high, have several protective factors. We compared HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C), HDL3-cholesterol (HDL3-C), apo A-I, and apo A-II in octogenarians and younger control subjects smoking less than 10 cigarettes/d and not taking drugs known to affect lipid metabolism. Using a new procedure, we also compared the levels of Lp A-I and Lp A-I/A-II. The cholesterol content of total HDL was similar in octogenarian and control (38 +/- 8 years) men while HDL2-C was higher and HDL3-C, apo A-I, and A-II were lower in octogenarian than in control men. In women, the level of HDL-C and apo A-I was similar in premenopausal and octogenarian subjects but higher in postmenopausal women than in octogenarians, while HDL2-C and apo A-II were similar in the three groups. In contrast, HDL3-C was higher in the two groups of control women (premenopausal and postmenopausal) than in octogenarians. However, Lp A-I was significantly elevated in octogenarian men and women (men: 61 +/- 14 mg/dL; women: 70 +/- 14 mg/dL) by comparison with younger control subjects (men: 48 +/- 12 mg/dL; premenopausal women: 53 +/- 11 mg/dL; postmenopausal women: 63 +/- 19 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Oxidation of lipoproteins and atherosclerosis.

The fatty streak is the earliest lesion of atherosclerosis. This lesion contains foam cells which are primarily derived from blood monocytes. The accumulation of cholesterol in macrophages is explained by the uptake of modified low-density lipoprotein (LDL). An in vivo modification of lipoproteins might be oxidation. The oxidized LDL showed several chemicophysical modifications. The first demonstrated effect of LDL oxidation was its increased susceptibility to uptake by cultured macrophages. Furthermore, oxidized LDL exhibits a chemotactic activity, and a cytotoxicity. An hypothesis that explains the appearance and development of atherosclerotic lesions and is based on obtained in vitro is exposed. LDL-like lipoproteins extracted from human aorta had some of properties of oxidized LDL, such as the recognition of materials present in atheroma by antibodies against oxidized LDL and the presence of autoantibodies against oxidized LDL in human sera are in favor of the pathogenetically important role of the oxidation of LDL.

Arteriosclerosis↗
PubMed1991

Plasma concentrations of apolipoprotein A-I containing particles in normolipidaemic young men.

Low levels of plasma high-density lipoprotein (HDL)-cholesterol and apolipoprotein (apo)-A-I are associated with premature coronary heart disease. However, particles in the density range of HDL are heterogeneous. Two main types of apo A-I-containing particles can be identified, one species containing both apo A-I and apo A-II (Lp A-I:A-II) and the other apo A-I but no apo-A-II (Lp A-I). This study was designed to measure HDL cholesterol, apo A-I, and, using a new procedure, Lp A-I in 233 healthy normolipidaemic young men (cholesterol less than 250 mg dl-1 and triglycerides less than 200 mg dl-1). Among these subjects, the composition of HDL was very variable as indicated by the 10th and the 90th percentiles of the HDL-cholesterol/apo A-I ratios which were 0.32 and 0.49, respectively. The 10th and 90th percentiles of apo A-I and Lp A-I:A-II were 126 and 167 mg dl-1 and 83 and 116 mg dl-1, respectively. On the other hand, Lp A-I showed a much larger variation, the 10th and 90th percentiles being at 33 and 62 mg dl-1, respectively. The distribution of individual values of Lp A-I showed that this fraction of apo A-I-containing particles was very variable among subjects, the Lp A-I/apo A-I ratio extending from 0.18 to 0.58. Triglycerides, Lp A-I and Lp A-I:A-II were correlated with HDL cholesterol, but no correlation between apo A-I containing subfractions and plasma triglycerides was noticed. Since preliminary results from angiographic and clinical studies show that Lp A-I could exert a protective role for atherosclerosis, it would seem that the measurement of Lp A-I might help in the future to characterize better the individual's risk for atherosclerosis.

Adolescent↗
PubMed1990

Compound heterozygote for lipoprotein lipase deficiency: Ser----Thr244 and transition in 3' splice site of intron 2 (AG----AA) in the lipoprotein lipase gene.

Cloning and sequencing of translated exons and intron-exon boundaries of the lipoprotein lipase gene in a patient of French descent who has the chylomicronemia syndrome revealed that he was a compound heterozygote for two nucleotide substitutions. One (TCC----ACC) leads to an amino acid substitution (Ser----Thr244), while the other alters the 3' splice site of intron 2 (AG----AA). The functional significance of the Thr244 amino acid substitution was established by in vitro expression in cultured mammalian cells.

Amino Acid Sequence↗
PubMed1989

[Cholesterol: from where does it come, how does it circulate, where does it go?].

Cholesterol is an essential component of cell membranes. It is present in food and partially absorbed by the gut, but it is also synthesized by every cell in the body. However, only enterocytes and hepatocytes play a quantitatively important role in the synthesis of cholesterol that is present in plasma. Cholesterol is transported by complex particles, called lipoproteins, which have specific proteins on their surface. These proteins, called apolipoproteins, have an essential function in the metabolism of lipoproteins. Low-density lipoproteins (LD) transport the majority of cholesterol in normal human plasma and distribute it to peripheral tissues. They bind to a specific cell receptor (LDL-receptor), and after endocytosis the intracellular cholesterol will be used to build cell membranes and to synthesize other molecules (biliary acids, hormones). The cholesterol present in peripheral tissues is taken up by high-density lipoproteins (HDL) and transferred to LDL. The latter particles are then degraded by the liver, and cholesterol is excreted in the bile.

Cholesterol↗
PubMed1989

[Regulation of blood cholesterol, mechanism of hypercholesterolemia].

The concentration of plasma cholesterol essentially reflects the level of low-density lipoproteins (LDL). This LDL level is a function of genetic factors (LDL receptors, apolipoprotein E phenotype) and environmental factors, notably diet. A high plasma level of LDL is one of the major risk factors for coronary disease. A decreased catabolism and/or an increased LDL synthesis may be responsible for abnormally high plasma LDL levels. Among mechanisms of decreased LDL catabolism, deficiency in LDL receptors is the best known and corresponds to familial hypercholesterolaemia. The presence of antibodies to the LDL receptor has been described, and abnormalities in the regulation of LDL receptor number are probably frequent. The latter abnormalities can be amplified by a diet enriched with lipids. A mutation in apolipoprotein B100 decreasing the binding of LDL to its receptor has been shown to be responsible for hypercholesterolaemia. Hypercholesterolaemia by increased LDL synthesis is known, but it may result from primary abnormalities in the regulation of apo-B100 synthesis or be secondary to another lipid modification.

Apolipoproteins↗
PubMed1989

Effect of simvastatin on plasma lipids, apolipoproteins and lipoprotein particles in patients with primary hypercholesterolaemia.

The effect of treatment with simvastatin, a new HMG-CoA reductase inhibitor, has been investigated in 27 patients with primary hypercholesterolaemia. It produced a significant decrease of cholesterol and phospholipids in plasma, LDL and apolipoprotein B-containing lipoproteins. Plasma apolipoproteins B, C-III and E were also significantly lowered. The concentration of lipoprotein particles recognized by monoclonal antibodies (BL3, BL5 and BL7), associated with atherosclerotic disease, was also lowered by the treatment. Lipoproteins LpA-II:A-I were not changed, while LpA-I, which has been suggested to be the protective fraction of the apo A-I-containing lipoproteins, was slightly and inconsistently increased.

Adolescent↗
PubMed1989

Characterization of five mouse monoclonal antibodies to apolipoprotein[a] from human Lp[a]: evidence for weak plasminogen reactivity.

We describe the development of five murine monoclonal antibodies (14A12, 39A1, 53A9, 73A7, and 128A6) specific to human apolipoprotein[a] (Mr approximately 570,000), and their characterization by a number of procedures including cotitration, competition and inhibition enzyme-linked immunosorbent assays (ELISA), immunoblotting of native lipoproteins and of SDS-solubilized apolipoproteins electrophoresed in polyacrylamide gels, and dot immunobinding assays. The patterns of immunoreactivity of these antibodies were similar. Each reacted in ELISA assays and upon electroimmunoblotting with purified apo[a], with apo[a] liberated by reduction of Lp[a], and with delipidated Lp[a] solubilized in SDS, but by contrast, they reacted with native Lp[a] to a significant degree only upon electroimmunoblotting. No reactivity was seen with LDL-apoB-100 or with other apolipoproteins. The cross-reactivity of these antibodies with the homologous protein, plasminogen, was examined by comparison of the amount of plasminogen or apo[a] required for 50% inhibition of antibody binding to apo[a], and by an ELISA assay. The inhibition assay showed reactivity with plasminogen to be 37- to 50-fold lower than with apo[a], while dot immunobinding showed the lower limit of detection of plasminogen and of apo[a] to be approximately 320 and 31 micrograms, respectively. In an ELISA sandwich assay based on monoclonal antibodies LHLP-1, 14A12, and 53A9, the lower limit of Lp[a] detection (approximately 1 ng/ml protein) was about 100-fold less than that of plasminogen. Chemical modification of apo[a] revealed a significant contribution of arginine residues to the epitopes of 14A12, 39A1, and 53A9. Modification of cysteine residues with iodoacetamide was without effect, thereby distinguishing these antibodies from LHLP-1. Each antibody reacted with the six major size forms of apo[a] (Mr approximately 450,000-750,000) in immunoblots of human sera electrophoresed in SDS-polyacrylamide gels. Marked heterogeneity in apo[a] phenotype was detected and both single and double band phenotypes were observed in a randomized study. Cotitration and competition binding studies showed varying degrees of interaction between all five epitopes, with the exception of 128A6 which appeared to be independent of 39A1 and 53A9 (and vice versa). These data suggest that our five monoclonal antibodies recognize epitopes on apolipoprotein[a] that are exposed and accessible on the native Lp[a] particle. We conclude that our monoclonal antibodies recognize a specific region of apo[a], and that this region undergoes a conformational change upon adsorption of Lp[a] to plastic thereby diminishing epitope recognition.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

A selective bi-site immunoenzymatic procedure for human Lp[a] lipoprotein quantification using monoclonal antibodies against apo[a] and apoB.

A selective bi-site ELISA assay procedure for quantification of Lp[a] lipoprotein in human plasma based on linkage of apo[a] to apoB is described. The lipoproteins referred to as apo[a]:B were captured by a mixture of two anti-apo[a] monoclonal antibodies (K07, K09) and were revealed by a mixture of six anti-apoB monoclonal antibodies coupled to peroxidase. Since apo[a] and plasminogen have striking similarities in protein structure, the selective binding of Lp[a]:B in our assay depended upon the marked difference in affinity of the K07 and K09 mixture for Lp[a]:B (Kd = 0.32 x 10(-10) M) versus plasminogen (Kd = 0.47 x 10(-7)M). The high sensitivity (the Lp[a]:B working range 0.06-0.40 micrograms/ml) and the use of anti-apoB as antibody tracer added to the selectivity of the assay. The expression of K07 and K09 epitopes determined by competitive inhibition method and the reactivity of Lp[a]:B particles measured by bi-site ELISA were similar on individual lipoproteins, independent to their plasma levels. The assay is precise, and intra- and interassay coefficients of variation were 4.7% and 9.6%, respectively. It yields quantitative Lp[a]:B values that correlate highly with Lp[a] levels obtained by electroimmunoassay with polyclonal antibody (r = 0.73) or with Lp[a] levels measured by the other bi-site ELISA using only K07 and K09 antibodies (r = 0.96). However, upon analyzing each individual plasma with an arbitrary Lp[a]-cut off of 15 mg/dl, evidence of the qualitative aspect of the lipoprotein was obtained. The group with Lp[a] less than 15 mg/dl had higher frequency of subjects (65%) with the ratio Lp[a]/Lp[a]:B above 1.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1988

Further resolution and comparison of the heterogeneity of plasma low-density lipoproteins in human hyperlipoproteinemias: type III hyperlipoproteinemia, hypertriglyceridemia and familial hypercholesterolemia.

The heterogeneity of the plasma low-density lipoproteins (LDL) in subjects with type III hyperlipoproteinemia (3 cases), with hypertriglyceridemia (4 cases) and with the heterozygous form of familial hypercholesterolemia (FH, 4 cases) has been evaluated using a new, high resolution equilibrium density gradient ultracentrifugation procedure. The mass distribution profile, physicochemical properties, particle heterogeneity and apoprotein B content of a series of 13 LDL subfractions was examined in the 3 hyperlipidemic groups and the data were compared with those reported earlier in normolipidemic subjects. In FH, LDL mass was distributed as a narrow peak of d approximately 1.031-1.034 g/ml, whereas the distribution in hypertriglyceridemia was markedly asymmetric with a single peak of elevated density (d approximately 1.037-1.043 g/ml); the distribution in type III subjects was distinguished by its bi- or trimodal nature and broad profile. The chemical composition of LDL gradient subfractions in FH and in hypertriglyceridemia markedly resembled that of the respective parent LDL of d = 1.019-1.063 g/ml, displaying elevated proportions of cholesteryl ester in FH and of protein in hypertriglyceridemia. LDL subfractions in type III disease were enriched in free cholesterol. The Stokes diameters of LDL particles in corresponding subfractions from the 3 hyperlipidemic states were similar; however, whereas a single particle species was characteristic of each LDL subfraction in both FH and in our normolipidemic group, 2 species were frequently present in each subfraction in both type III and type IV diseases; in addition, subfractions from type III subjects occasionally exhibited 3 size species. Apolipoprotein B-100 was the predominant protein component in LDL subfractions from all 3 hyperlipidemic groups. Plasma LDL consist then of multiple particle species which constitute a particularly complex spectrum in type III hyperlipoproteinemia and in hypertriglyceridemia. The origin(s) of such particle subspecies is indeterminate at present; moreover, they may differ in their intravascular metabolism, in their degradation in tissues and in their relative atherogenicities.

Adolescent↗