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Biomedical subjects

F Soubrier

Publications and source records attributed to F Soubrier.

At least 55 records · Page 3Linked to original sources
PubMed1998

[Polymorphism of the renin-angiotensin-aldosterone system: molecular and epidemiogenetic aspects].

The involvement of polymorphic variations in the structure of the renin angiotensin aldosterone system genes in the predisposition to cardiovascular disease is a particularly important field of investigation. A large number of studies have been published and their results are often contradictory. It is therefore important to identify the functional variants modifying the level of expression of these genes or the structure of the encoded proteins. This will allow the clear quantitation of their effect on quantitative phenotypes both in vitro and in vivo. It is also important to study in the future new phenotypes, particularly dynamic phenotypes, potentially influenced by these genotypes and to use them for building a new cardio-vascular pharmacogenetics.

Aldosterone↗
PubMed1997

Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.

Pregnancy-induced hypertension may be regarded as a manifestation of endothelial-cell dysfunction. The role of the eNOS gene in the development of a familial pregnancy-induced hypertension was evaluated by analysis of linkage among affected sisters and in multiplex families (n = 50). Markers from a 4-cM region encoding the eNOS gene showed distortion from the expected allele sharing among affected sisters (P = .001-.05), and the statistic obtained from the multilocus application of the affected-pedigree-member method also showed distortion (T[f(P)=sqrt(P)] = 3.53; P < .001). A LOD score of 3.36 was obtained for D7S505 when a best-fitting model derived from genetic epidemiological data was used, and LOD scores of 2.54-4.03 were obtained when various other genetic models were used. Estimates of recombination rate, rather than maximum LOD-score values, were affected by changes in the genetic parameters. The transmission-disequilibrium test, a model-free estimate of linkage, showed strongest association and linkage with a microsatellite within intron 13 of the eNOS gene (P = .005). These results support the localization of a familial pregnancy-induced hypertension-susceptibility locus in the region of chromosome 7q36 encoding the eNOS gene.

Adult↗
PubMed1997

Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10.

Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because of its high prevalence (e.g. 15-20% of the European and American populations). Although blood pressure is known to have a strong genetic determination, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci involved in blood pressure regulation have been found by linkage in experimental hereditary hypertensive rat strains, but their relationship to human hypertension has not been extensively investigated. One of the principal blood pressure loci has been mapped to rat chromosome 10 and we have undertaken an investigation of the homologous region on human chromosome 17 in familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant evidence of linkage ( P <0.0001 in some analyses) near two closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal to the ACE locus in the homology region. Our results indicate that chromosome 17q could contain a susceptibility locus for human hypertension and show that comparative mapping may be a useful approach for identification of such loci in humans.

Animals↗
PubMed1997

Genetic studies of the renin-angiotensin system in arterial hypertension associated with non-insulin-dependent diabetes mellitus.

OBJECTIVE: To determine whether angiotensinogen (AGT) and angiotensin II type 1 (AT1) receptor genes contribute to the development of arterial hypertension in members of French Caucasian families and in subjects with hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: Sibpair linkage analyses were performed with microsatellites near the AGT and AT1 receptor genes in 179 hypertensive sibpairs from 69 NIDDM kindreds. In addition, population/association studies were performed with the M235T and T174M polymorphisms of the AGT gene, and the A1166C polymorphism of the AT1 receptor gene. RESULTS: No evidence for linkage between the AGT and AT1 receptor loci and hypertension was observed. In addition, the distributions of genotypes of AGT and AT1 receptor gene polymorphisms did not differ significantly among a group of unrelated individuals with both hypertension and NIDDM (n = 188) and three groups of unrelated control subjects with NIDDM (n = 117), hypertension (n = 75) or none of these conditions (n = 125). CONCLUSIONS: These results suggest that the AGT and AT1 receptor genes are not major genetic determinants of hypertension associated with NIDDM in this population, although we can not exclude the possibility that these loci make a minor contribution in a polygenic context.

Aged↗
PubMed1997

The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk.

OBJECTIVE: This meta-analysis attempted to derive pooled estimates for the associations between various cardiovascular-renal disorders and the deletion/insertion (D/I) polymorphism of the angiotensin converting enzyme (ACE) gene. METHODS: Case-control studies were combined, using the Mantel-Haenszel approach. Joint P values for continuous variables were calculated by Stouffer's method. Continuous measurements reported in different units were expressed on a percentage scale using the within-study mean of the II genotype as the denominator. RESULTS: The computerized database used for this analysis included 145 reports with an overall sample size of 49 959 subjects. Overall, possession of the D allele was associated with an increased risk of atherosclerotic and renal microvascular complications. In comparison with the II reference group, the excess risk in DD homozygotes (P < 0.001) was 32% for coronary heart disease (CHD; 30 studies), 45% for myocardial infarction (20 studies), 94% for stroke (five studies) and 56% for diabetic nephropathy (11 studies). The corresponding risk in DI heterozygotes amounted to 11% (P= 0.02), 13% (P= 0.02), 22% (P= 0.10) and 40% (P < 0.001), respectively. Hypertension (23 studies), left ventricular hypertrophy (five studies), hypertrophic or dilated cardiomyopathy (eight studies) and diabetic retinopathy (two studies) were not related to the DI polymorphism. Publication bias was observed for CHD, myocardial infarction and microvascular nephropathy, but not hypertension. In studies with DNA amplification in the presence of insertion-specific primers, the risk associated with the DD genotype increased to 150% [95% confidence interval (CI) 76-256; four studies] for diabetic nephropathy, but decreased to 12% (95% CI -3 to 28; seven studies) for CHD and 14% (95% CI -6 to 37; four studies) for myocardial infarction. On the other hand, the pooled odds ratios did not materially change if the meta-analysis was limited to articles published in journals with an impact factor of at least 4. Furthermore, compared with the II control group, the circulating ACE levels (29 studies) were raised 58 and 31% (P < 0.001) in DD and DI subjects, respectively. In contrast, plasma renin (10 studies), systolic and diastolic blood pressure (46 studies) and body mass index (30 studies) were not associated with the D allele. CONCLUSION: The D allele is not associated with hypertension, but behaves as a marker of atherosclerotic cardiovascular complications and diabetic nephropathy. These associations do not necessarily imply a causal relationship and may have been inflated by publication bias. Nevertheless, their possible therapeutic implications may be subject to further investigation in prospective (intervention) studies.

Alleles↗
PubMed1997

Circulating and cellular markers of endothelial dysfunction with aging in rats.

The influence of age on endothelial functional markers was investigated in rats. Angiotensin I converting enzyme (ACE) activity and nitric oxide synthase (NOS) mRNA expressions were examined in the lung and aorta of 10-, 20-, and 30-mo-old normotensive rats. These data were extended by the measurement of circulating endothelial cells. ACE activity was significantly decreased in plasma (P < 0.01) and lungs (P < 0.01) at 30 mo, whereas it was significantly increased in the aorta (P < 0.001) at this age. Conversely, ACE mRNA levels decreased with age in the lung (P < 0.05). The level of constitutive endothelial NOS (eNOS) mRNA was significantly reduced in the aorta of 30-mo-old rats (P < 0.05), but no changes were observed in the lungs. The level of inducible NOS (iNOS) mRNA in the aorta was significantly decreased in 20- and 30-mo-old rats (P < 0.01), whereas it was significantly increased in the lung at 30 mo (P < 0.01). Interestingly, eNOS was expressed approximately 30 times more (P < 0.001) in the aorta than iNOS, whereas in the lung it was only slightly higher than iNOS (35%; P < 0.001). Neuronal NOS mRNA expression was not modified with aging. In the aorta, guanosine 3',5'-cyclic monophosphate concentration followed NOS expressions and showed a significant decrease at 30 mo (P < 0.001). An increase in the number of circulating endothelial cells was observed in the oldest rats, possibly reflecting an increase in endothelial cell turnover with aging. The present results demonstrate that aging modifies the expression of endothelial markers implicated in the regulation of vasomotor tone. This age-dependent impairment of endothelial functions could contribute to the increased risk of pathological processes within the arterial wall associated with aging.

Aging↗
PubMed1997

Molecular genetics of the renin-angiotensin-aldosterone system in human hypertension.

Blood pressure is a quantitative trait that varies along a continuum in the general population and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Family studies and twin studies suggest that about 30% of blood pressure variance is attributable to genetic factors and 50% to environmental factors. Two forms of hypertension transmitted on an autosomal recessive basis have been identified: one is glucocorticoid-suppressible hyperaldosteronism (GSH) and the other is Liddle's syndrome (amiloride-suppressible hyperactivity of the epithelial sodium channel). The molecular basis for these two forms of severe hypertension has recently been elucidated. GSH is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. Apart from these rare genetic defects, a number of susceptibility genes can increase the risk of hypertension in a given environment. Their presence is neither necessary nor sufficient to cause hypertension. The best documented example is the angiotensinogen gene. Angiotensiongen is the substrate of renin, and the renin-angiotensinogen reaction is the first and limiting step in the pathway that leads to production of angiotensin II, a peptide with important effects on blood pressure control and the metabolism of water and sodium. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension or hypertension of pregnancy. The M235T variant of angiotensinogen is more prevalent among hypertensive than among normotensive subjects in several Caucasian and Japanese populations. The M235T variant is also associated with plasma angiotensinogen elevation, which is potentially responsible for increased production of angiotensin II. In other terms, relationships exist between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distal phenomenon (i.e., blood pressure elevation). DNA libraries for the study of hypertension have been set up, and many informative genetic markers distributed along the genome have been identified. Using position cloning techniques, these markers could be used in the search for genetic links between arterial hypertension and a chromosomal locus.

Angiotensinogen↗
PubMed1997

[Role of genetics in the risk assessment of hypertensive patients].

The identification of genes responsible for the predisposition to hypertension could help define the exact role of genetics in the risk assessment of hypertensive subjects. Large scale genetic epidemiological trials and recent advances in the knowledge of the human genome should resolve this problem in the years to come. In addition to the role of each gene, the interaction between genes and the environment will have to be defined in the context of the physiopathology of this condition. The identification of genes which may favourise the complications of hypertension is an objective as important for definition of risks as for the management of the disease.

Animals↗
PubMed1996

Drosophila melanogaster angiotensin I-converting enzyme expressed in Pichia pastoris resembles the C domain of the mammalian homologue and does not require glycosylation for secretion and enzymic activity.

Drosophila melanogaster angiotensin I-converting enzyme (AnCE) is a secreted single-domain homologue of mammalian angiotensin I-converting enzyme (ACE) which comprises two domains (N and C domains). In order to characterize in detail the enzymic properties of AnCE and to study the influence of glycosylation on the secretion and enzymic activity of this enzyme, we overexpressed AnCE (expression level, 160 mg/l) and an unglycosylated mutant (expression level, 43 mg/l) in the yeast Pichia pastoris. The recombinant enzyme was apparently homogeneous on SDS/PAGE without purification and partial deglycosylation demonstrated that all three potential sites for N-linked glycosylation were occupied by oligosaccharide chains. Each N-glycosylation sequence (Asn-Xaa-Ser/Thr) was disrupted by substituting a glutamine for the asparagine residue at amino acid positions 53, 196 and 311 by site-directed mutagenesis to produce a single mutant. Expression of the unglycosylated mutant in Pichia produced a secreted catalytically active enzyme (AnCE delta CHO). This mutant displayed unaltered kinetics for the hydrolyses of hippuryl-His-Leu, angiotensin 1 and N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and was equally sensitive to ACE inhibitors compared with wild-type AnCE. However, AnCE delta CHO was less stable, displaying a half-life of 4.94 h at 37 degrees C, compared with AnCE which retained full activity under the same conditions. Two catalytic criteria demonstrate the functional resemblance of AnCE with the human ACE C domain: first, the kcat/Km of AcSDKP hydrolysis and secondly, the kcat/Km and optimal chloride concentration for hippuryl-His-Leu hydrolysis. A range of ACE inhibitors were far less potent towards AnCE compared with the human ACE domains, except for captopril which suggests an alternative structure in AnCE corresponding to the region of the S1 subsite in the human ACE active sites.

Amino Acid Sequence↗
PubMed1996

Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients.

BACKGROUND: Clinical and experimental studies have demonstrated a major role of the renin-angiotensin system in the functional and structural changes of the large arteries in hypertension. Because genetic studies may help us to understand the mechanisms underlying the involvement of this system in arterial regulation, the present study was designed to assess the contribution of polymorphisms of the ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AGTR1 A 1166C) genes on aortic stiffness regulation. METHODS AND RESULTS: This study included 311 untreated hypertensive and 128 normotensive subjects. Aortic stiffness was evaluated by measurement of the carotid-femoral pulse-wave velocity (PWV). In normotensive subjects, the two polymorphisms did not influence any of the studied parameters. In hypertensive subjects, there was a decreasing trend of mean PWV with the number of ACE D alleles, but this association became significant only after adjustment for blood pressure (P < .05). Conversely, the AGTR1 A 1166C polymorphism was independently associated with aortic stiffness. Mean values of PWV were 11.6 +/- 2.7 m/s in AGTR1 AA homozygotes, 13.3 +/- 3.3 m/s in AC heterozygotes, and 15.3 +/- 4.3 m/s in CC homozygotes (P < .0001 and P < .00001 after adjustment for age and mean blood pressure, respectively). The percentage of variance of PWV explained by AGTR1 A 1166C polymorphism (11.6%) was much larger than that of ACE I/D polymorphism (1.7%). CONCLUSIONS: These results suggest that in hypertensive but not normotensive subjects, the AGTR1 and ACE genotypes are involved in the regulation of aortic rigidity. The presence of the AGTR1 C allele is a strong independent determinant of aortic stiffness, whereas presence of the ACE 1 allele is weakly associated with increased stiffness.

Adolescent↗
PubMed1996

A study of chimeras constructed with the two domains of angiotensin I-converting enzyme.

Angiotensin I-converting enzyme (ACE) is composed of two highly similar domains called the N and C domains, which display some contrasting enzymatic properties. We constructed two ACE chimeras: chimera 1, comprised of the N domain containing the central 60 amino acid residues of the C domain, and chimera 2, comprised of the C domain containing the central 60 amino acid residues of the N domain. Chimeras 1 and 2 displayed Km values for Hip-His-Leu and Z-Phe-His-Leu and kcat ratios for these two substrates similar to that of the N and C domains, respectively. Thus, the short sequence exchanged between the two domains does not confer the specific properties of that domain for these two substrates but, rather, such specific properties must arise from the sequences surrounding the central region in each domain.

Amino Acid Sequence↗
PubMed1996

Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow.

Physiological adaptation of normal blood vessels to acute or chronic changes in blood flow is endothelium dependent. In vitro studies have shown that, among other genes, NO synthase (NOS) 3 mRNA and protein expression is enhanced by acute elevation of shear stress in endothelial cells. We have investigated the effect of chronic high blood flow on NOS3 mRNA and protein expression in rat aorta. NOS3 mRNA levels were measured by quantitative polymerase chain reaction (PCR) in the aortas of 12 rats with arteriovenous fistulas and 9 sham-operated control rats. The PCR assay indicated that NOS3 mRNA levels were significantly enhanced (twofold) during high blood flow. Western blots showed that immunoreactive NOS3 levels were also increased to a similar extent. Furthermore, the Ca(2+)-dependent NOS activity, measured by the L-arginine to L-citrulline conversion assay, and the cGMP content were also significantly increased in the proximal aortic wall submitted to the arteriovenous shunt. These results indicate that NOS3 mRNA and protein expression is enhanced in vivo during chronic high blood flow.

Animals↗
PubMed1996

Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis.

Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage desequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms could be divided into two groups: five polymorphisms in the 5' region and three in the coding sequence and the 3' UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5' group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT)2/3 polymorphism. The second QTL would have a frequency of approximately .20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants.

Adolescent↗
PubMed1996

[Genetics of cardio-vascular complications of diabetes].

Variations of glucose level represent the major cause of diabetic micro- and macroangiopathy, but other factors play a significant role on the occurrence of the complications, which is difficult to quantify. We will review the genetic factors which modulate vascular and heart response to diabetes. In an attempt to modelize a complex disease, we will distinguish susceptibility gene for the deleterious effects of hyperglycemia, through advanced glycation end-products (AGE), and genes responsible for associated and interacting, diseases, such as hypertension and atherosclerosis. We examine, in particular, the possible interactions of the products of these genes on target organs.

Angiotensinogen↗
PubMed1996

The vascular wall as a target for association studies by the candidate gene approach.

The implication of polymorphisms of candidate genes in the variation of quantitative traits can be studied by using marker genotypes in association studies. The vascular wall properties, such as wall thickness and compliance, can be approached by such strategies. A rational choice of candidate genes can be based on an extensive knowledge of the cellular and biochemical processes occurring in the vascular wall. Molecular cloning and the availability of markers on several genes allow the investigation of a large number of candidate genes. This review summarizes the knowledge of some aspects of cell proliferation and differentiation in the vascular wall and the results already obtained by association studies on vascular wall phenotypes.

Animals↗