Essential Hypertension In Men Research Articles

The role of obesity in the implementation of genetic predisposition to the development of essential hypertension in men

BACKGROUND: Obesity is considered a non-infectious pandemic, and the increase in its spread is a serious medical and social problem. High values of body mass index closely correlate with arterial hypertension and its complications, but the effect of obesity on the realization of hereditary susceptibility to essential hypertension (EH) remains poorly understood.
 AIMS: To study the associations of polymorphic loci of MMPs with the development of EH in men depending on the presence of obesity.
 MATERIALS AND METHODS: The study was conducted in a case-control design. Surveyed 821 men 564 patients with hypertension and 257 patients of the control group. Groups of patients and controls were divided into subgroups depending on the presence of obesity. All men were genotyped for eight polymorphic loci of MMPs. Nonsynonymous SNPs were detected using the software SIFT (https://sift.bii.a-star.edu.sg/). The regulatory potential was studied using the HaploReg service (https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php). The association of SNPs with the expression level was detected using GTEx-portal (http://www.gtexportal.org).
 RESULTS: It was found that in obese men allele A (OR=2.01; p=0.01) and genotype GG (OR=0.42, p=0.01) of rs11568818 MMP7 are associated with the essential hypertension. In men without obesity allele 6A (OR=1.32; p=0.04) of rs3025058 MMР3 and genotypes GG (OR=1.52; p=0.04) and GA (OR=0.63; p=0.03)) of rs17577 MMP9 are associated with the development of the disease. These SNPs located in region of promoter and enhancer histone marks, in the region of hypersensitivity to DNAse-1, in binding sites of regulatory proteins and transcription factors. These SNPs associated with the level of gene expression.
 CONCLUSIONS: In this study we established associations with the development of EH of SNP rs11568818 MMP7 in obese men and of SNPs rs3025058 MMР3 and rs17577 MMP9 in non-obese men.

Study of associations of polymorphism of matrix metalloproteinases genes with the development of arterial hypertension in men

The aim of research. To study the association of polymorphic loci of matrix metalloproteinases with the development of essential hypertension (EH) in men of the Central Chernozem Region of Russia. Materials and methods. A study of 564 men with EH and 257 control men was performed. Analysis of the polymorphic loci of metalloproteinases rs11568818 MMР7, rs1320632 MMР8, rs11225395 MMР8, rs1799750 MMР1, rs3025058 MMР3 was performed using real-time PCR. The study of associations of SNPs and their haplotypes with the development of arterial hypertension was carried out using logistic regression analysis in the PLINK software (v. 2.050). The regulatory potential of polymorphic loci was analyzed in the HaploReg software (v. 4.1) (http://archive.broadinstitute.org). The effect of SNP on gene expression was studied using the data of the Genotype-Tissue Expression project (http://www.gtexportal.org/). Results. Haplotype including rs11568818 MMP7, rs1320632 MMP8, rs11225395 MMP8 and rs1799750 MMP1 associated with a high risk of disease in men (OR=2,58, pperm=0,04). These polymorphisms located in region of promoter and enhancer histone marks and in the region of hypersensitivity to DNAse-1. They located in sites of proteins bound (TBP, CJUN, CFOS and GATA2) and they associated with the level of gene expression ММР7, ММР27 and RP11-817J15.3 (in peripheral blood, skeletal muscles, nervous tissue and other). Сonclusion. Haplotype G-A-C-1G for polymorphisms rs11568818 MMP7, rs1320632 MMP8, rs11225395 MMP8, rs1799750 MMP1 are associated with the development of essential hypertension in men in the Central Chernozem Region of Russia.

Genetic determinants of essential hypertension in the population of Tatars from Russia.

Systemic inflammation and impaired function of endothelium play an important role in the development of hypertension. Our study aimed to analyze an association between essential hypertension and polymorphic markers in candidate genes in the group of 530 Tatars from the Republic of Bashkortostan, Russia. The study group consisted of 216 male patients with essential hypertension (mean age 48.92 ± 8.8 years) and 314 healthy individuals of corresponding sex and age without history of cardiovascular disease. Association between studied polymorphisms and essential hypertension was analyzed using PLINK. We detected an association between EDNRB rs5351, VEGFA -2549(18)I/D, and ADRB2 rs1042713 polymorphisms and essential hypertension in men of Tatar ethnic origin. EDNRB, VEGFA, and VCAM1 single-nucleotide polymorphisms were associated with SBP and DBP. However, only EDNRB rs5351 remained associated with hypertension after Bonferroni correction for multiple testing. A Markov chain Monte Carlo-based approach implemented in the APSampler program was used to analyze association of genotype and/or allele combinations with disease. The most influential in conferring risk of hypertension was EDNRBG/G+ADRB2A+VCAM1A combination (odds ratio = 4.15, PBonf = 5.43 × 10). Our results suggest that rs5351 single-nucleotide polymorphism is a strong independent predictor of essential hypertension in men of Tatar ethnic origin.

Hereditary features of plasma concentrations of endothelin-1 in men with hypertension and chronic heart failure

Objective. To improve diagnosis of the severity of essential hypertension in men by determining the plasma levels of ET-1 in patients with different ET-1 gene variants.Materials and methods. We examined 191 men aged 40–60 years old, who live in Podillia region in Ukraine. Among them 79 men from control group, 62 men with uncomplicated essential hypertension (EH) with left ventricular hypertrophy (LVH) and 50 men with EH and chronic heart failure (CHF) II-III functional classes by NYHA. We used clinical, biochemical, instrumental and mathematical methods of investigation, polymerase chain reaction and enzyme immunoassay.Results. In both healthy men and patients with EH Lys/Lys genotype and the Lys allele of the ET-1 gene dominates. It was found that any inherited variant of the ET-1 gene was not associated with the risk of developing EH and CHF on its background. In patients with EH the peptide level was significantly higher than in the control group and the highest concentration of ET-1 was in patients with EH and CHF. In men from the control group, patients with uncomplicated EH with LVH and EH with CHF – carriers of genotype Lys/Lys – plasma concentration of ET-1 was significantly lower than in owners of the Asn allele. In carriers of Lys/Lys genotype the highest level of the peptide in plasma is determined in patients with EH complicated by CHF. In owners of the Asn allele concentration of ET-1 in men with EH was significantly higher than in control subjects, but the difference between patients with EH was not found. In men with uncomplicated EH with LVH, who are carriers of Lys/Lys genotype the 2d degree of arterial hypertension (AH) is significantly more common, and in carriers of the Asn allele the 3d degree of AH. In patients with EH and CHF carriage of the Asn allele is associated with 3d degree of AH.Conclusions. Lys/Lys genotype and the Lys allele of the ET-1 gene dominate among control group and patients with EH. The carriers of the Asn allele of the ET-1 gene have significantly higher plasma levels of the aforementioned peptide among the control group and in the patients with EH. The Asn allele is associated with 3d degree of AH. The ET-1 boundary levels were estimated, that can be used for screening of large contingents of people for early diagnosis of EH and CHF.

THE LEVEL OF CIRCULATING TESTOSTERONE AND THE BLOOD-PLASMA LIPID PROFILE IN MEN WITH ESSENTIAL HYPERTENSION, CARRIERS OF GG GENOTYPE IN RELATION TO THE -257T>G POLYMORPHIC MARKER OF THE CLOCK GENE

We have previously established the connection of the -257T>G (rs4865010) polymorphic marker of the CLOCK gene with the risk of essential hypertension (EH) (stage I–II, grade 1–2) and coronary artery disease (acute myocardial infarction). This polymorphic marker is a single nucleotide substitution of thymine with guanine in the CLOCK gene promoter. It has been shown that men, carriers of GG genotype for this marker, had a significantly higher risk of EH. Based on the literature and our own research, we assumed that one of the possible mechanisms behind the increased risk of EH in men with GG genotype according to the -257T>G polymorphic marker of the CLOCK gene is a decrease in testosterone levels in blood, which, according to the literature, may be associated with changes in lipid profiles. Therefore, we carried out a comparative analysis of the levels of circulating testosterone and blood-plasma lipoproteins in men with different genotypes in relation to the -257T>G polymorphic marker (rs4865010) of the CLOCK gene from the group of patients diagnosed with EH (stages I–II, grade 1–2) and the control group. It was shown that men with EH, carriers of GG genotype in relation to the -257T>G polymorphic marker of the CLOCK gene, have testosterone levels corresponding to androgen-deficient state, which at present is considered to be a risk factor for cardiovascular complications. It was revealed that the reduced level of circulating testosterone in men with this genotype is associated with a reduced level of the anti-atherogenic plasma lipid fraction (HDL–C).

Hemodynamic and hormonal patterns of untreated essential hypertension in men and women

Knowledge of hemodynamic factors accounting for the development of hypertension should help to tailor therapeutic approaches and improve blood pressure control. Few data exist regarding sex differences of hemodynamic factors contributing to hypertension progression among patients with untreated nondiabetic stage I and II prehypertension (PreHyp) as defined by the Joint National Committee-7 guidelines (JNC-7). We utilized noninvasive impedance cardiography, applanation tonometry and plasma measures of angiotensin II, angiotensin (1-7), serum aldosterone, high-sensitivity C-reactive protein (hs-CRP) and cytokine biomarkers of inflammation to characterize the hemodynamic and hormonal profile of 100 patients with untreated hypertension (39 women). Despite there being no differences between women and men in terms of office blood pressure, heart rate and body mass index, men demonstrated lower values of pulse pressure, systemic vascular resistance, brachial artery pulse wave velocity and augmentation index. In each of the three hypertension categories, the increased blood pressure in men was associated with significant augmentations in stroke volume and cardiac output compared with women. Sex-related hemodynamic differences were associated in women with higher plasma levels of leptin, hs-CRP, plasma angiotensin II and serum aldosterone, and no differences in the serum concentrations of cytokinins. In women but not men, hs-CRP correlated with plasma concentrations of transforming growth factor β1 (TGFβ1) and body weight; in addition, plasma TGFβ1 correlated with levels of serum vascular cell adhesion molecule 1. The impact of sex differences in the hemodynamic factors accounting for the elevation in arterial pressure in subjects with essential hypertension has been poorly characterized or this information is not available. We suggest that this gap in knowledge may adversely influence choices of drug treatment since our study shows for the first time significant differences in the hemodynamic and hormonal mechanisms accounting for the increased blood pressure in women compared to men.

CYP2E1 Gene Promoter Polymorphism -1293G>C Increases the Risk of Essential Hypertension in Men with Alcohol Abuse

We studied the association between of cytochrome P450 2E1 (CYP2E1) gene polymorphism and risk of essential hypertension development depending on alcohol drinking habit in unrelated men in Russian population (patients with essential hypertension and healthy volunteers). All participants were genotyped for four CYP2E1 gene polymorphisms -1293G>C (rs3813867), -1053C>T (rs2031920), 7632T>A (rs6413432), and 9896C>G (rs2070676) by PCR and restriction analysis. We found statistically significant associations between -1293C allele (OR=5.04, 95% CI=1.23-20.70, p=0.03) and -1293GC genotype (OR=5.36, 95% CI=1.28-22.50, p=0.03) with increased risk of essential hypertension in men. Stratified analysis on alcohol drinking habit showed that the presence of -1293C allele (OR=6.82, 95% CI=1.12-41.70, p=0.04) and -1293GC genotype (OR=7.61, 95% CI=1.2-48.4, p=0.03) in men with alcohol abuse increases the risk of essential hypertension. The obtained data suggest that excessive alcohol consumption and increased induction of cytochrome in the carriers of -1293C allele of CYP2E1 gene lead to generation of highly reactive free radical oxidation products. These processes induced oxidative stress and endothelial induction, which served as the pathogenetic basis for essential hypertension.

Purification and mechanism of action of “cortexin,” a novel antihypertensive protein hormone from kidney and its role in essential hypertension in men

Because kidney tissue damage is associated with both hypertension and impaired nitric oxide (NO) production, we investigated the possibility whether the kidney tissue contains any activator of endothelial NO synthase (eNOS) that could be important in essential hypertension. An activator protein of M r 43000 Da for eNOS from the goat kidney cortex homogenate was purified to homogeneity by chromatographic techniques. This activator trivially, called “cortexin,” was determined by enzyme-linked immunosorbent assay using anticortexin antibody. NO was determined by the formation of methemoglobin. Injection of 0.5 nmol cortexin/kg body weight to rabbit pretreated with l-epinephrine that increased the systolic and diastolic pressures to 195 ± 3.40 mm Hg and 98.14 ± 6.64 mm Hg, respectively, reduced and kept the elevated pressures at normal ranges of 133.57 ± 12.14 (systolic) and 51.03 ± 3.21 (diastolic) for 45 hours with simultaneous increase of plasma NO level. The inhibition of cortexin-induced NO synthesis nullified the antihypertensive effect of cortexin. The plasma cortexin level in newly diagnosed persons with essential hypertension was 0 pmol/mL (median), which contrasted with 218.94 pmol cortexin/mL (median), in normotensive persons ( P < .0005; n = 25). We concluded that the impaired production of cortexin in the cortex of kidney might lead to essential hypertension.

Association between prostaglandin E2 receptor gene and essential hypertension

Background Essential hypertension (EH) is a complex multifactorial polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. In the kidney, prostaglandins (PGs) are important mediators of vascular tone and salt and water homeostasis, and are involved in the mediation and/or modulation of hormonal action. In previous studies, mice deficient in the prostaglandin E2 (PGE 2) EP2 receptor had resting systolic blood pressure (BP) that was significantly lower than that of wild-type controls. The BP of those mice increased when they were put on a high-salt diet, suggesting that the EP2 receptor is involved in sodium handling by the kidney. In the present study, we investigated the association between EH and nucleotide polymorphisms in the gene encoding the prostaglandin E2 receptor subtype EP2 (PTGER2). Methods We selected three single-nucleotide polymorphisms (SNP) in the human PTGER2 gene (rs1254601, rs2075797, and rs17197), and we performed a genetic association study of 266 EH patients and 253 age-matched normotensive (NT) controls. Results There was no significant difference in overall distribution of genotypes or alleles of any of the SNP between the EH and NT groups. However, among men, the A/A type of the SNP rs17197 (rs17197, A/G in 3′UTR) was significantly more frequent in EH subjects than in NT subjects ( P=0.041). Conclusion The present findings suggest that rs17197 is useful as a genetic marker of EH in men.

Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men

Gap junctions, formed by connexins (Cx), are important in the regulation of vascular tone. Previously, we reported two closely linked polymorphisms (-44G --> A and +71A --> G) within regulatory regions of the gene for Cx40, a major connexin in the vascular wall and the kidney. In the present study, we examined the hypothesis that these polymorphic variants are associated with hypertension and that they interact with blood pressure in healthy individuals. Cx40 genotypes were determined in 191 subjects with essential hypertension, 198 normotensive individuals, and a healthy control population (178 twin pairs, 108 monozygotic, 70 dizygotic). We found a significant contribution of the minor Cx40 allele or genotype (-44AA/+71GG) to the risk of hypertension in men (P = 0.013 or P = 0.035; odds ratio, 1.87 or 2.10, respectively), but not in women. Moreover, in the healthy control population a significant effect of Cx40 genotype and sex on systolic blood pressure was found (P < 0.05 and P < 0.0001, respectively). Women carrying the minor Cx40 genotype had significantly higher systolic blood pressure compared with non-carriers (P < 0.05). In men, systolic blood pressure in carriers of the minor Cx40 genotype was not significantly different from the other two genotypes, possibly because of the small number of men in this group. However, men carrying the -44GA/+71AG genotype had higher standing systolic blood pressure compared with the more common Cx40 genotype (-44GG; P = 0.033). These findings suggest that the Cx40 polymorphisms may form a genetic susceptibility factor for essential hypertension in men.

Deletion polymorphism in the gene for angiotensin-converting enzyme is associated with essential hypertension in men born during the Pacific War

Age is a strong risk factor for hypertension in relation to vascular aging. Additional etiological factors include: lifestyle, genetic factors, and their interactions. The aim of this study is to examine whether an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene is associated with essential hypertension in Korean born during the Pacific War. A total of 13,914 healthy subjects (8261 men, 5653 women) aged 20–79 years were examined. Subjects with abnormal renal, thyroid dysfunction, or electrolyte levels were excluded. Logistic regression analysis showed increased risk (OR = 1.15; 95% CI, 1.01–1.31) in men, but not in women (OR, 1.06; 95% CI, 0.89–1.26). However, after adjustment for age, obesity, cholesterol, alcohol consumption, and diabetes mellitus, increased risk in men was not significant (OR, 1.13; 95% CI, 0.98–1.42). Analyzed according to birth-year, DD genotype showed increased risk for hypertension in only a subgroup of men (adjusted OR, 1.56; 95% CI, 1.16–2.09; p = 0.001), born during the Pacific War (1941–1945 year). Findings suggest that the ACE DD genotype plays a role in the pathogenesis of essential hypertension, in conjunction with adverse environmental conditions in early life, with sex-related difference.

Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men : the Suita Study.

The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (ACE DD) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites. Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between ACE DD and hypertension. The frequency of DD (17.1%) in hypertensive men was significantly higher (P<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (DD vs II) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72). Despite the lower frequency of the DD genotype in Japanese than in whites, the ACE gene polymorphism was associated with increased risk for hypertension, suggesting that this polymorphism is a mild but certain genetic risk factor for essential hypertension in men.

"Salt-sensitive" essential hypertension in men. Is the sodium ion alone important?

We investigated whether the anionic component of an orally administered sodium salt can influence the salt's capacity to increase blood pressure. In five men with essential hypertension in whom blood pressure was normal with restriction of dietary sodium chloride to 10 mmol per day (0.23 g of sodium per day), oral administration of sodium chloride for seven days, 240 mmol per day (5.52 g of sodium per day), induced significant increases in systolic and diastolic blood pressures, of 16 +/- 2 and 8 +/- 2 mm Hg (mean +/- SEM), respectively (P less than 0.05). An equimolar amount of sodium given as sodium citrate induced no change in blood pressure. Replacing supplemental sodium chloride with an equimolar amount of sodium as sodium citrate abolished the increase in blood pressure induced by sodium chloride. Both salts induced substantial and comparable sodium retention, weight gain, and suppression of plasma renin activity and plasma aldosterone, but supplemental sodium chloride increased plasma volume and urinary excretion of calcium, whereas sodium citrate did not. These preliminary findings demonstrate that the anionic component of an orally administered sodium salt can influence the ability of that salt to increase blood pressure, possibly by determining whether the salt induces an increase in plasma volume. Our observations in a small group of men with salt-sensitive hypertension will require confirmation in larger numbers of patients of both sexes.

Studies on Prediction of Hypertension in Spontaneously Hypertensive Rats (SHR)

Urinary Na excretion following acute peroral water loading was clearly increased in SHRSP and SHR compared with WKY even at the age of 4 weeks before the development of hypertension. Cold exposure before and after adrenal denervation did not affect such water-induced exaggerated natriuresis which, therefore, might possibly be involved in genetic mechanism or disposition to hypertension. Since these hypertensive models are prone to retain Na intracellularly (Yamori: In Hypertension; Physiopathology and Treatment: 556-581, 1983), acute water loading may enhance urinary Na excretion. This phenomenon observed even in prehypertensive stage can be utilized as a predictor for hypertension in SHR and SHRSP and possibly for essential hypertension in men.

Haemodynamic Changes Associatedc with Obesity and High Blood Pressure in Crats with Ventromedial Hypothalamic Lesions

1. The haemodynamic and plasma volume changes associated with obesity and high blood pressure were studied in nine male rats with electrolytic ventromedial hypothalamic lesions and their paired sham-operated controls. Body weight and arterial pressure were greater in the rats with ventromedial hypothalamic lesions (565 +/- 16 vs 462 +/- 14 g, P < 0.001; 128 +/- 3 vs 118 +/- 3 mmHg, P < 0.05, respectively). Cardiac output was slightly elevated, and that portion of cardiac output distributed to the kidneys was reduced (P < 0.001). Plasma volume was contracted in the rats with ventromedial hypothalamic lesions (21.0 +/- 0.1 vs 2.8 +/- 0.1 ml/100 g, P < 0.001). 2. The haemodynamic characteristics of rats in which obesity and mild hypertension have been induced by electrolytic ventromedial hypothalamic lesion are similar to mild obesity essential hypertension in men.

Study on cerebrospinal fluid catecholamines in hypertensive disease

Total catecholamines adrenaline (A) and noradrenaline (NA), were determined in twenty-four patients with essential hypertension (EH) (ten men, fourteen women) and sixteen controls (healthy subjects, patients suffering from other diseases, but with normal blood pressure, and patients with secondary hypertension: arteriosclerosis or renal). Blood catecholamines in the controls yielded the following values: 0.84 μg % 0 (M) and 1.35 (W); in EH 0.91 (M) and 1.61 (W); in the CSF of the controls: 4.60 μg % 0 (M) and 5.14 (W); in EH 3.96 (M) and 7.67 (W). Control values were 5.4 (M) and 3.8 times (W) higher in the CSF than in the blood; in EH they were 4.4 (M) and 4.7 (W) higher. In EH in men, NA was 3.6 times higher in the CSF than in the blood, and in the controls 5.5 times higher. A was 5.4 times higher in EH and 4.2 times higher in the controls. Similar values were obtained in women (NA 3.5 as against 4.6 and A 6 as against 2). In EH, CSF A was 55 % (M) and 59 % (W) and in the blood 45 % (M) and 42% (W) of total catecholamines; in the controls A was only 22 % (M) and 23 % (W) in the CSF, as against 38 % (M) and 41 % (W) in the blood.