The T8590C polymorphism of CYP4A11 and 20-hydroxyeicosatetraenoic acid in essential hypertension

A role for a deficit in transport actions of 20-hydroxyeicosatetraenoic acid (20-HETE) in hypertension is supported by the following: (1) diminished renal 20-HETE in Dahl-S rats; (2) altered salt- and furosemide-induced 20-HETE responses in salt-sensitive hypertensive subjects; and (3) increased population risk for hypertension in C allele carriers of the T8590C polymorphism of CYP4A11, which encodes an enzyme with reduced catalytic activity. We determined T8590C genotypes in 32 hypertensive subjects, 25 of whom were phenotyped for salt sensitivity of blood pressure and insulin sensitivity. Urine 20-HETE was lowest in insulin-resistant, salt-sensitive subjects (F=5.56; P<0.02). Genotypes were 13 TT, 2 CC, and 17 CT. C allele frequency was 32.8% (blacks: 38.9%; whites: 25.0%). C carriers (CC+CT) and TT subjects were similarly distributed among salt- and insulin-sensitivity phenotypes. C carriers had higher diastolic blood pressures and aldosterone:renin and waist:hip ratios but lower furosemide-induced fractional excretions of Na and K than TT. The T8590C genotype did not relate to sodium balance or pressure natriuresis. However, C carriers, compared with TT, had diminished 20-HETE responses to salt loading after adjustment for serum insulin concentration and resetting of the negative relationship between serum insulin and urine 20-HETE to a 1-microg/h lower level of 20-HETE. The effect of C was insulin independent and equipotent to 18 microU/mL of insulin (Delta20-HETE= 2.84-0.054xinsulin-0.98xC; r(2)=0.53; F=11.1; P<0.001). Hence, genetic (T8590C) and environmental (insulin) factors impair 20-HETE responses to salt in human hypertension. We propose that genotype analyses with sufficient homozygous CC will establish definitive relationships among 20-HETE, salt sensitivity of blood pressure, and insulin resistance.     

The V433M variant of the CYP4F2 is associated with ischemic stroke in male Swedes beyond its effect on blood pressure

Cytochrome (CYP) 4A11 and CYP4F2 are responsible for renal production of 20-hydroxyeicosatetraenoic acid, a vasoconstrictor and natriuretic substance. The CYP4A11 F434S and CYP4F2 V433M polymorphisms reduce 20-hydroxyeicosatetraenoic acid production in vitro. The aim of the present study was to evaluate the effect of these polymorphisms on blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. The polymorphisms were genotyped in the cardiovascular cohort of the Malm? Diet and Cancer Study. The incidence of cardiovascular events (coronary events, n=276; ischemic stroke, n=199) was monitored over 10 years of follow-up. The analysis of BP levels was performed twice: either excluding or including subjects under antihypertensive treatment. In the whole population, CYP4A11 S434S homozygotes had higher systolic BP, both crude and adjusted for the number of antihypertensive drugs, and higher prevalence of hypertension with respect to F434 carriers. Male, but not female, CYP4F2 M433 carriers had significantly higher crude and adjusted systolic and diastolic BPs and a trend toward higher hypertension prevalence (P=0.06) with respect to V433V homozygotes. After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male CYP4F2 M433 carriers was significantly higher with respect to V433V homozygotes (hazard ratio: 1.69; 95% CI: 1.10 to 2.60) even when baseline BP levels and hypertension prevalence were included in the Cox proportional hazard model. A common CYP4F2 V433M polymorphism might increase the risk of incident ischemic stroke in male subjects only partially through its elevating effect on BP. Additional studies are needed to confirm these data.     

CYP4A11 gene T8590C polymorphism is associated with essential hypertension in the male western Chinese Han population

Background: CYP4A11 is a member of the cytochrome P450 enzymes and is responsible for metabolizing arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in the regulation of blood pressure. This study aimed to evaluate whether or not the CYP4A11 gene polymorphism T8590C (rs1126742) is involved in essential hypertension in the western Chinese Han population.

Methods: In a case-control study, the participants included 864 (523 males and 341 females) patients with essential hypertension and 661 (422 males and 239 females) healthy subjects. The T8590C polymorphism of the CYP4A11 gene was analyzed by using the TaqMan® SNP Genotyping Assay.

Results: For men, the frequencies of the CC genotype and the C allele were higher in essential hypertension than in the control group (p?=?0.022 and p?=?0.016, respectively). After adjustment of confounding factor such as diabetes, smoking, BMI, TG and TC, the significant difference was observed in CC genotype (OR?=?1.897, 95% confidence interval [CI] 1.026–3.508; p?=?0.041). No difference was found in all participants and females.

Conclusions: The CC genotype and C allele were associated with essential hypertension in the male western Chinese Han population.     

A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men

OBJECTIVE: CYP4A11, a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in blood pressure regulation in humans. Disruption of the murine cyp4a14 and cyp4a10 genes, homologues of human CYP4A11, was reported recently to cause hypertension. The gene-disrupted male mice had higher blood pressure than the gene-disrupted female mice. The present study aimed to assess the association between the human CYP4A11 gene and essential hypertension, using a haplotype-based case-control study including separate analysis of the gender groups. METHODS: The 304 essential hypertension patients and 207 age-matched control individuals were genotyped for three single-nucleotide polymorphisms of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). Data were assessed for three separate groups: total participants, men and women. RESULTS: For total participants, the genotypic distribution of rs1126742 differed significantly between the two groups (P = 0.005). For total participants, men and women, the recessive model (CC versus TC + TT) of rs1126742 differed significantly between the two groups (P = 0.007, P = 0.043, and P = 0.045, respectively). Logistic regression analysis showed the TC + TT genotype was significantly higher in essential hypertension patients than in control individuals for total participants and men (P = 0.022 and P = 0.043, respectively). The A-T-G haplotype frequency (established by rs2269231, rs1126742, rs9333025) was significantly higher in essential hypertension men than in control men (P = 0.043). CONCLUSIONS: Essential hypertension is associated with the TC + TT genotype of rs1126742 in the human CYP4A11 gene. The A-T-G haplotype appears a useful genetic marker of essential hypertension in Japanese men.     

Association of a functional polymorphism in the CYP4A11 gene with systolic blood pressure in survivors of myocardial infarction

OBJECTIVE: Survivors of myocardial infarction (MI) are known to have a high prevalence of arterial hypertension which, at the same time, imposes a major risk to such patients. Genetic variants of the arachidonic acid monooxygenase CYP4A11 may result in decreased synthesis of 20-hydroxyeicostatetraenoic acid (20-HETE), experimental hypertension and elevated blood pressure levels in humans. The present study aimed to investigate the impact of the functionally relevant T8590C polymorphism of this gene on blood pressure and the prevalence of hypertension in MI patients. METHODS: Survivors of MI from the MONICA Augsburg MI registry (n = 560) were studied after a mean of 5.6 years after the acute event. Participants were examined by standardized anthropometric and echocardiographic measurements, as well as genotyping for CYP4A11 T8590C allele status. RESULTS: Genotype frequencies in MI patients (TT = 71.8%, CT = 26.2%, CC = 2.0%) did not differ from those in population-based controls (n = 1363; TT = 75.4%, CT = 22.5% and CC = 2.1%, P = 0.22). MI survivors with the CC genotype displayed higher systolic blood pressure levels (CC: 143.4 +/- 4.9 mmHg versus CT: 134.5 +/- 1.3 mmHg and TT: 131.1 +/- 0.8 mmHg; P = 0.02) and a non-significant trend towards higher diastolic blood pressure levels (CC: 88.4 +/- 3.0 mmHg versus CT: 84.9 +/- 0.8 mmHg and TT: 83.9 +/- 0.5 mmHg; P = 0.17) in multivariate models. Accordingly, the C allele was related to elevated odds ratios for hypertension in a recessive [4.14; 95% confidence interval (CI) = 1.07-15.96, P = 0.04] and in a dominant model (1.50; 95% CI = 1.03-2.20, P = 0.04), respectively. No blood pressure-independent association of the T8590C polymorphism with echocardiographic parameters of left ventricular function and/or geometry was found. CONCLUSION: The data obtained in the present study strengthen the evidence of an association of the CYP4A11 T8590C polymorphism with blood pressure levels and hypertension prevalence. Particularly, the risk of arterial hypertension is substantially higher in MI patients homozygous for the CC allele. By contrast, no evidence was obtained for an association between this genotype and MI.     

A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population

CYP4A11 oxidizes arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite with renovascular and tubular function in humans. A previous study demonstrated a significant association between the CYP4A11 gene polymorphism and hypertension; however, the precise mechanism of the association has not been clarified. To assess the involvement of CYP4A11 in the pathogenesis of hypertension, we sought to identify a functional polymorphism of CYP4A11 and examined its impact on predisposition to hypertension in the Tanno-Sobetsu Study. The -845A/G polymorphism was identified in the promoter region of CYP4A11 by direct sequencing. Luciferase expression driven by the promoter of CYP4A11 containing the wild-type -845GG genotype was 30% lower than expression with the variant -845AA genotype. Gel mobility shift assays with nuclear protein extracts showed specific binding to probes containing the variant -845GG. To assess the effect of CYP4A11 polymorphisms on hypertension, we also carried out a case-control study using 4 single nucleotide polymorphisms (-845A/G, -366C/T, 7119C/T, and 8590T/C) in the Tanno-Sobetsu Study. The odds ratio for hypertension in participants with the AG+GG genotype of -845A/G was 1.42 (P=0.008), and the odds ratio for hypertension of the TT genotype of 7119C/T was 1.37 (P=0.037) after adjusting for confounding factors. The haplotype-based case-control analysis using 4 single nucleotide polymorphisms revealed a significant haplotype (G-C-T-T) that was significantly associated with hypertension, with an odds ratio of 1.44 (P=0.006) after adjusting for confounding factors. We have identified a functional variant (-845A/G) of CYP4A11 that is significantly associated with hypertension and that appears to be a novel candidate for a predisposing factor for hypertension.     

Haplotype-based case study of human CYP4A11 gene and cerebral infarction in Japanese subject

OBJECTIVE: CYP4A11 is an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, which is involved in regulation of vascular tone in the brain. Recent evidence indicates that the polymorphism of the CYP genes is associated with cerebral infarction (CI). The aim of the present study was to assess the association between the human CYP4A11 gene and CI using a haplotype-based case-control study divided by gender. METHODS: Three SNPs of the human CYP4A11 gene (rs2269231, rs1126742, and rs9333025) were selected and genotyped for 174 CI patients and 293 controls. The data were assessed for three separate groups: total subjects, men and women. RESULTS: In men, the genotype distribution of rs9333025 significantly differed between the CI patients and control subjects (P = 0.047). The distribution of the dominant model of rs9333025 (GG vs. GA + AA) significantly differed between both the total and the men groups (P = 0.033, P = 0.028, respectively). Logistic regression analysis adjusted for the history of hypertension and diabetes mellitus also showed that the GG genotype was significantly more frequent in the CI patients than in the controls, both for the total and men groups (P < 0.001, P = 0.008, respectively). The overall distribution of the haplotypes constructed with the 3 SNPs showed significant differences between the CI and the control in total group (P = 0.049). The T-C-G haplotype was significantly more frequent in control subjects than in the CI patients in the total group (P = 0.020). CONCLUSIONS: The GG genotype of rs9333025 could be a genetic marker for CI in Japanese men. In addition, the T-C-G haplotype might also be a protective marker for CI in Japanese.     

Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy

Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (n=1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 T8590C allele status. Individuals with the CC genotype have higher systolic (CC 141.4+/-3.17 mm Hg versus CT 134.2+/-0.97 mm Hg and TT 134.3+/-0.53 mm Hg; P=0.03) and diastolic blood pressure levels (CC 85.4+/-2.06 mm Hg versus CT 80.3+/-0.63 mm Hg and TT 80.7+/-0.34 mm Hg; P=0.02). Accordingly, the odds ratio (adjusted for age, body mass index, and gender) of the CC genotype versus the CT and TT genotypes for hypertension was 3.31 (95% confidence interval [CI]), 1.38 to 7.96; P=0.016) in the entire study population, with similar trends in men (4.30 [95% CI, 1.08 to 17.15]) and women (2.93 [95% CI, 0.88 to 9.84]). Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function.     

Association between the CYP3A5 genotype and blood pressure

We tested the hypothesis that the presence of a CYP3A5*1 allele is associated with increases in blood pressure in 2 studies of subjects with a total of 683 participants. The first study involving 271 subjects was part of a longitudinal study conducted at Indiana University Medical Center that consisted of 2 phases. The first phase studied the relationship of salt sensitivity with blood pressure, whereas the second phase, conducted approximately 26 years later, studied the relationship between blood pressure, carbohydrate intolerance, and vascular compliance in the same subjects. The second study was a cross-sectional evaluation of 412 normotensive and hypertensive subjects conducted at the University of California San Diego. The second study (Mantel-Haenszel chi(2) test; P=0.05) showed that a greater proportion of black participants with poor blood pressure control had CYP3A5*1/*1 genotype. Evaluation of the untreated blood pressure from phase 1 of the first study showed that the blacks with CYP3A5*3/*3 (146+/-35 mm Hg) had a higher systolic blood pressure than those with the *1/*3 (119+/-14.1 mm Hg; P=0.0006) and *1/*1 (125+/-17.4 mm Hg; P=0.009) genotypes. For blacks in study 2, the CYP3A5*1 allele was more common in hypertensives (Fisher exact test; P=0.025) than normotensives. In whites there was no association between CYP3A5 genotype and blood pressure in either study. We conclude that although untreated blood pressure may be higher in blacks with the CYP3A5*3/*3 genotype, the CYP3A5*1 allele may be associated with hypertension that is more refractory to treatment in this ethnic group.     

Endothelial dysfunction and hypertension in rats transduced with CYP4A2 adenovirus

Vascular cytochrome P450 (CYP) 4A enzymes catalyze the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid which participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor and myogenic stimuli. This study was undertaken to investigate the consequences of CYP4A overexpression on blood pressure and endothelial function in rats treated with adenoviral vectors carrying the CYP4A2 construct. Intravenous injection of Adv-CYP4A2 increased blood pressure (from 114+/-1 to 133+/-1 mm Hg, P<0.001), and interlobar renal arteries from these rats displayed decreased relaxing responsiveness to acetylcholine, which was offset by treatment with an inhibitor of CYP4A. Relative to data in control rats, arteries from Adv-CYP4A2-transduced rats produced more 20-HETE (129+/-10 versus 97+/-7 pmol/mg protein, P<0.01) and less nitric oxide (NO; 4.2+/-1.6 versus 8.4+/-1 nmol nitrite+nitrate/mg; P<0.05). They also displayed higher levels of oxidative stress as measured by increased generation of superoxide anion and increased expression of nitrotyrosine and gp91phox. Collectively, these findings demonstrate that augmentation in vascular 20-HETE promotes the development of hypertension and causes endothelial dysfunction, a condition characterized by decreased NO synthesis and/or bioavailability, imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, and enhanced endothelial activation.     

Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans

An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (−6.3 ± 7.3/−3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P < .01/<.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings.     

中国北方汉族人群CYP4F2基因rs2108622多态性与原发性高血压的相关性研究

目的：探讨我国北方汉族人群CYP4F2基因单核苷酸多态性位点rs2108622与原发性高血压的相关性。方法：采用病例-对照研究的方法,选取在北京安贞医院就诊的北方汉族原发性高血压者765例（HT组）和同期健康体检血压正常者477例（NT组）。应用TaqMan荧光定量法对CYP4F2基因rs2108622进行基因分型,评估该多态性位点与我国北方汉族人群原发性高血压发病风险的关系。结果：rs2108622位点在HT组和NT组的基因型分别为AA型61/35、AG型296/162、GG型403/273;A等位基因频率分别为27.5%/24.7%,G等位基因频率分别72.5%/75.3%。两组间基因型和等位基因频率分布,差异均无统计学意义（分别为P=0.218,P=0.123）。多因素Logistic回归分析显示：等位基因模型（OR=1.147,95%CI=0.853!1.543）、显性模型（OR=0.788,95%CI=0.549!1.131）、隐性模型（OR=1.153,95%CI=0.549!2.422）、纯合子模型（OR=1.018,95%CI=0.48!2.157）、加性模型（OR=0.872,95%CI=0.649!1.172）均未发现该多态性位点与原发性高血压存在相关性。根据性别进行亚组分析显示：男性亚组中A等位基因频率在HT组（27.5%）高于NT组（23.7%）,但差异无统计学意义（P=0.096）。而在女性亚组中各基因型和等位基因频率分布两组间比较,亦均差异无统计学意义（P=0.579和P=0.677）。结论：本研究发现CYP4F2基因rs2108622多态性位点可能与中国北方汉族人群原发性高血压的发病不存在相关性。     

Lack of association between genetic polymorphism of CYP11B2 and hypertension in Japanese: the Suita Study.

Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a polymorphism in the 5'-flanking region of the CYP11B2 gene [T(-344)C] has been reported to be associated with blood pressure and plasma aldosterone levels. We investigated the association between this polymorphism and hypertension in a large population-based sample of 4,000 Japanese. The genotype distribution in hypertensive subjects (n=1,535) was compared to that in normotensive subjects (n=2,514). In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. All analyses were performed separately for men and women. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of C allele: 30.3% vs. 31.4%, p=0.48) or women (31.5% vs. 31.7%, p=0.93). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the T(-344)C polymorphism of CYP11B2 is unlikely to influence blood pressure status in the Japanese population.     

Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population

BACKGROUND: The aldosterone synthase gene (CYP1B2) locus is a candidate region involved in the development of hypertension. OBJECTIVE: To study the relationship between the C-344T CYP1B2 polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. DESIGN: Population-based, cross-sectional study of 1313 middle-aged men and women (456 white, 441 of African origin and 416 South Asian). Anthropometry, blood pressure, biochemistry, questionnaire data and timed urine collections were taken with standardized techniques. All were genotyped for the C-344T CYP11B2 polymorphism. RESULTS: The frequency of the C allele was significantly lower in people of African origin (0.21) than in white (0.46) and South Asian (0.43) (P < 0.001). After adjustment for age, sex and ethnicity the TT genotype was associated with 14% higher plasma aldosterone levels, 3.7 mmHg higher systolic and 2.1 mmHg higher diastolic blood pressure than CC (P for linear trend < 0.05). No significant interactions with age, sex, ethnicity, body mass index (BMI) and fractional excretion of sodium were found in the associations between genotype and both blood pressure and aldosterone levels. In a sub-sample of participants in which plasma renin activity was measured (n = 457), a significant excess of T alleles was found in those with a raised (>/= 750) aldosterone-to-renin ratio (ARR). CONCLUSION: In this multi-ethnic population, the C-344T CYP1B2 polymorphism is associated with blood pressure, plasma aldosterone levels and ARR. Although significant differences in allele frequencies were found between groups, ethnicity does not explain the results.     

人细胞色素P450 4A11基因核心启动子区的鉴定

目的研究细胞色素P4504A11基因启动子区对该基因转录活性的影响。方法运用生物信息学的方法预测细胞色素P4504A11基因启动子区的重要调控序列，然后采用5’侧翼区缺失的方法将包含重要调控序列的启动子克隆到双报告基因载体中，用脂质体转染HepG2细胞，24h后检测荧光素酶相对活性。然后使用Alibaba 2．0Transfae4．0预测增强子区域可能存在的转录因子结合位点。结果·36--720-＋1、-972～＋1、-1039-＋1区域的启动子活性较高，其中-972～＋1区域最强，与此相比-536-＋1、-720～＋1荧光素酶相对活性分别下降了96．9％和70．1％。结论人CYP4A11基因5’侧翼区的影响转录活性的启动子关键区域位于-972--720bp范围内。     

Ovariectomy, but not estrogen deficiency, increases CYP4A modulation of alpha(1)-adrenergic vasoconstriction in aging female rats

BACKGROUND: Postmenopausal women are more likely to develop cardiovascular disease (CVD) than premenopausal women. Increased vasoconstriction in the peripheral vasculature may underlie this risk. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). CYP4A modulation of alpha(1)-adrenergic vasoconstriction is increased in aging male rats; however, this pathway has not been investigated in aging females. To generate an appropriate model of menopause, we ovariectomized aged Sprague-Dawley rats to create an aged, ovarian-depleted phenotype. Because estrogen has profound effects on the peripheral vasculature, we also determined the effect of estrogen replacement on CYP4A modulation of vasoconstriction. METHODS: Aged (15-16 months) rats were assigned to be intact or ovariectomized. Ovariectomized rats received either placebo (OVX) or 17beta-estradiol (OVX-E) subcutaneously for 4 weeks. Mesenteric arteries were isolated and constricted with the alpha(1)-adrenergic agonist phenylephrine or intraluminal pressure in the absence or presence of the CYP4A inhibitor, DDMS. RESULTS: Ovariectomy increased CYP4A modulation of alpha(1)-adrenergic vasoconstriction. This was unaffected by estrogen replacement. Arteries from OVX-E animals exhibited increased phenylephrine sensitivity and forced dilation relative to arteries from intact and OVX animals. Myogenic tone was increased in both OVX and OVX-E animals relative to intact rats; however, CYP4A inhibition had no effect on myogenic tone in any group. CONCLUSIONS: In aged female rats, ovariectomy caused an increase in CYP4A modulation of alpha(1)-adrenergic vasoconstriction that was not prevented by estrogen replacement. Future study of these pathways may provide important targets for the prevention of CVD in aging women.     

Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene

CONTEXT: Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown. OBJECTIVE: Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism. DESIGN: We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus. PARTICIPANTS: Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband. MAIN OUTCOME MEASURES: We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype. RESULTS: The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001). CONCLUSIONS: Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.