Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. (1/218)

Significant correlation of body sodium and potassium with blood pressure (BP) may suggest a role for aldosterone in essential hypertension. In patients with this disease, the ratio of plasma renin to plasma aldosterone may be lower than in control subjects and plasma aldosterone levels may be more sensitive to angiotensin II (Ang II) infusion. Because essential hypertension is partly genetic, it is possible that altered control of aldosterone synthase gene expression or translation may be responsible. We compared the frequency of 2 linked polymorphisms, one in the steroidogenic factor-1 (SF-1) binding site and the other an intronic conversion (IC), in groups of hypertensive and normotensive subjects. In a larger population, the relationship of aldosterone excretion rate to these polymorphisms was also evaluated. In 138 hypertensive subjects, there was a highly significant excess of TT homozygosity (SF-1) over CC homozygosity compared with a group of individually matched normotensive control subjects. The T allele was significantly more frequent than the C allele in the hypertensive group compared with the control group. Similarly, there was a highly significant relative excess of the conversion allele over the "wild-type" allele and of conversion homozygosity over wild-type homozygosity in the hypertensive group compared with the control group. In 486 subjects sampled from the North Glasgow Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) population, SF-1 and IC genotypes were compared with tetrahydroaldosterone excretion rate. Subjects with the SF-1 genotypes TT or TC had significantly higher excretion rates than those with the CC genotype. The T allele was associated with higher excretion rates than the C allele. However, no significant differences were found in excretion rate between subjects of different IC genotype. Urinary aldosterone excretion rate may be a useful intermediate phenotype linking these genotypes to raised BP. However, no causal relationship has yet been established, and it is possible that the polymorphisms may be in linkage with other causative mutations.  (+info)

Lack of association between a polymorphism of the aldosterone synthase gene and left ventricular structure. (2/218)

BACKGROUND: Cardiac growth and function may be modulated in part by trophic effects of neurohormones. Specifically, aldosterone has been shown to stimulate the growth of cardiac myocytes and the accumulation of cardiac extracellular matrix proteins. Moreover, a variant of the aldosterone synthase gene (a cytosine/thymidine exchange at position -344 in the transcriptional regulatory region) has been associated with enlargement and disturbed filling of the left ventricle (LV) in a small sample of young white adults. The aim of the present study was to reinvestigate the implications of aldosterone synthase -344C/T allele status for serum aldosterone levels, blood pressure, and LV structure and function in large population-based samples. METHODS AND RESULTS: Individuals who participated in the echocardiographic substudy of the third MONICA (MONitoring trends and determinants in CArdiovascular disease) survey (n=1445) or in the second follow-up of the first MONICA survey (n=562) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for aldosterone synthase -344C/T allele status. In both surveys, the distribution of sex, age, arterial blood pressure, and body mass index was homogeneous in the aldosterone synthase genotype groups. Echocardiographic LV wall thicknesses, dimensions, and mass indexes were not significantly associated with a specific aldosterone synthase genotype. Likewise, no association was detectable with echocardiographic measures of LV systolic or diastolic function. Data were consistent in both samples and not materially different in subgroups defined by age, sex, or intake of antihypertensive medication. Finally, no significant association was observed for aldosterone synthase allele status and serum aldosterone levels in the group of 562 individuals. CONCLUSIONS: The data are not in favor of a significant contribution of the C/T exchange at position -344 in the aldosterone synthase transcriptional regulatory region to the variability of serum aldosterone levels, blood pressure, or cardiac size or function as found in 2 white population-based samples.  (+info)

Changes in the glomerulosa cell phenotype during adrenal regeneration in rats. (3/218)

In situ hybridization was used to examine cellular differentiation during rat adrenal regeneration, defining zona glomerulosa [cytochrome P-450 aldosterone synthase (P-450aldo) mRNA positive], zona fasciculata [cytochrome P-450 11beta-hydroxylase (P-45011beta) mRNA positive], or zona intermedia [negative for both but 3beta-hydroxysteroid dehydrogenase (3beta-HSD) mRNA positive]. After unilateral adrenal enucleation with contralateral adrenalectomy (ULE/ULA), the expression of all mRNA was reduced at 2 days. From 5 to 10 days, P-45011beta and 3beta-HSD mRNA increased while P-450aldo remained low; at 20 days, all mRNA were increased. From 2 to 10 days, cells adjacent to the capsule showed intermedia cell differentiation; by 20 days, the subcapsular glomerulosa cells reappeared. This suggests that after enucleation the glomerulosa dedifferentiates to zona intermedia. The experiment was repeated in rats where the postenucleation ACTH rise was prevented. Rats underwent ULE with sham ULA (ULE/SULA) or ULE/SULA with ACTH treatment. Adrenals from ULE/SULA rats expressed increased P-450aldo mRNA at 10 days and reduced P-45011beta mRNA and adrenal weight at 30 days. ACTH treatment reversed the pattern toward that seen in ULE/ULA. These findings show that the enucleation-induced dedifferentitation of the glomerulosa cell may result in part from elevated plasma ACTH and that prevention of dedifferentiation may result in impaired regeneration.  (+info)

Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. (4/218)

The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I-converting enzyme (ACE) gene [4656(CT)(2/3)], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. B(max) and K(D) values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT)(2/3) variant with plasma ACE levels was observed (P<0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (P=0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (P=0.02). No genotype effect of the AT1R A1166C polymorphism was detected either on the B(max) or the K(D) value of the Ang II receptors on platelets.  (+info)

Modulation of aldosterone biosynthesis by adrenodoxin mutants with different electron transport efficiencies. (5/218)

Aldosterone biosynthesis is highly regulated on different levels by hormones, potassium, lipid composition of the membrane and the molecular structure of its gene. Here, the influence of the electron transport efficiency from adrenodoxin (Adx) to CYP11B1 on the activities of bovine CYP11B1 has been investigated using a liposomal reconstitution system with truncated mutants of Adx. It could be clearly demonstrated that Adx mutants Adx 4-114 and Adx 4-108, possessing enhanced electron transfer abilities, produce increases in corticosterone and aldosterone biosynthesis. Based on the Vmax values of corticosterone and aldosterone formation, Adx 4-108 and Adx 4-114 enhance corticosterone synthesis 1.3-fold and aldosterone formation threefold and twofold, respectively. The production of 18-hydroxycorticosterone was changed only slightly in these Adx mutants. The effect of Adx 1-108 on the product patterns of bovine CYP11B1, human CYP11B1 and human CYP11B2 was confirmed in COS-1 cells by cotransfection of CYP11B- and Adx-containing expression vectors. It could be shown that Adx 1-108 enhances the formation of aldosterone by bovine CYP11B1 and by human CYP11B2, and stimulates the production of corticosterone by bovine CYP11B1 and human CYP11B1 and CYP11B2 also.  (+info)

Joint effects of an aldosterone synthase (CYP11B2) gene polymorphism and classic risk factors on risk of myocardial infarction. (6/218)

BACKGROUND: The -344C allele of a 2-allele (C or T) polymorphism in the promoter of the gene encoding aldosterone synthase (CYP11B2) is associated with increased left ventricular size and mass and with decreased baroreflex sensitivity, known risk factors for morbidity and mortality associated with myocardial infarction (MI). We hypothesized that this polymorphism was a risk factor for MI. METHODS AND RESULTS: We used a nested case-control design to investigate the relationships between this polymorphism and the risk of nonfatal MI in 141 cases and 270 matched controls from the Helsinki Heart Study, a coronary primary prevention trial in dyslipidemic, middle-aged men. There was a nonsignificant trend of increasing risk of MI with number of copies of the -344C allele. However, this allele was associated in a gene dosage-dependent manner with markedly increased MI risk conferred by classic risk factors. Whereas smoking conferred a relative risk of MI of 2.50 (P=0.0001) compared with nonsmokers in the entire study population, the relative risk increased to 4.67 in -344CC homozygous smokers (relative to nonsmokers with the same genotype, P=0.003) and decreased to 1.09 in -344TT homozygotes relative to nonsmokers with this genotype. Similar joint effects were noted with genotype and decreased HDL cholesterol level as combined risk factors. CONCLUSIONS: Smoking and dyslipidemia are more potent risk factors for nonfatal MI in males who have the -344C allele of CYP11B2.  (+info)

Baroreflex sensitivity and variants of the renin angiotensin system genes. (7/218)

OBJECTIVES: Because the renin-angiotensin-aldosterone system (RAS) modifies cardiovascular autonomic regulation, we studied the possible associations between baroreflex sensitivity (BRS) and polymorphism in the RAS genes. BACKGROUND: Wide intersubject variability in BRS is not well explained by cardiovascular risk factors or life style, suggesting a genetic component responsible for the variation of BRS. METHODS: Baroreflex sensitivity as measured from the overshoot phase of the Valsalva maneuver and genetic polymorphisms were examined in a random sample of 161 women and 154 men aged 41 to 61 years and then in an independent random cohort of 29 men and 37 women aged 36 to 37 years. An insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE), M235T variants of angiotensinogen (AGT) and two diallelic polymorphisms in the gene encoding aldosterone synthase (CYP11B2), one in the promoter (-344C/T) and the other in the second intron, were identified by polymerase chain reaction. RESULTS: In the older population, BRS differed significantly across CYP11B2 genotype groups in women (10.1 +/- 4.5, 8.7 +/- 3.8 and 7.1 +/- 3.2 ms x mm Hg(-1) in genotypes -344TT, CT and CC, respectively, p = 0.003 and 11.1 +/- 4.4, 8.9 +/- 4.1 and 7.5 +/- 3.4 ms x mm Hg(-1) in intron 2 genotypes 1/1, 1/2 and 2/2, respectively, p = 0.002), but not in men. No comparable associations were found for BRS with the I/D polymorphism of ACE or the M235T variant of AGT. In the younger population, BRS was even more strongly related to the CYP11B2 promoter genotype (p = 0.0003). The association was statistically significant both in men (p = 0.015) and in women (p = 0.03). CONCLUSIONS: Common genetic polymorphisms in the aldosterone synthase (CYP11B2) gene is associated with interindividual variation in BRS.  (+info)

Ontogeny of angiotensin II type 1 receptor and cytochrome P450(c11) in the sheep adrenal gland. (8/218)

In the present study we investigated the ontogeny of the expression of the type 1 angiotensin receptor (AT(1)R mRNA) and the zonal localization of AT(1)R immunoreactivity (AT(1)R-ir) and cytochrome P450(c11) (CYP11B-ir) in the sheep adrenal gland. In the adult sheep and in the fetus from as early as 90 days gestation, intense AT(1)R-ir was observed predominantly in the zona glomerulosa and to a lesser extent in the zona fasciculata, and it was not detectable in the adrenal medulla. AT(1)R mRNA decreased 4-fold between 105 days and 120 days, whereas AT(1)R mRNA levels remained relatively constant between 120 days and the newborn period. In contrast, both in the adult sheep and in the fetal sheep from as early as 90 days gestation, intense CYP11B-ir was consistently detected throughout the adrenal cortex and in steroidogenic cells that surround the central adrenal vein. In conclusion, we speculate that the presence of AT(1)R in the zona fasciculata, and the higher levels of expression of AT(1)R at around 100 days gestation, may suggest that suppression of CYP17 is mediated via AT(1)R at this time. The abundant expression of AT(1)R-ir and CYP11B-ir in the zona glomerulosa of the fetal sheep adrenal gland would also suggest that lack of angiotensin II stimulation of aldosterone secretion is not due to an absence of AT(1)R or CYP11B in the zona glomerulosa.  (+info)

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