Cyclophilin-A: a novel biomarker for untreated male essential hypertension

Abstract

Vascular cytokines, total nitrite, and cyclophilin-A (CyP-A) may be related to the pathogenesis of untreated hypertension. Forty males with normotensive and untreated essential hypertension were recruited in this cytokines survey. Body mass index (BMI), hyperlipidemia, and plasma CyP-A were increased in the hypertensive group (p?<?0.05). However, only BMI (p?=?0.022) and plasma CyP-A (p?=?0.020) were found to be significant contributors to hypertension by multiple regression analysis. CyP-A was also positively correlated with systolic blood pressure (p?=?0.029) and diastolic blood pressure (p?=?0.047). These findings indicated that plasma CyP-A is a critical molecular biomarker in the early pathogenesis of essential hypertension.     

Angiotensin-converting enzyme signalling in human preadipocytes and adipocytes

Angiotensin-converting enzyme (ACE, kininase II) is a plasma membrane zinc metallopeptidase that acts as a key enzyme for the extracellular conversion of vasoactive peptides. Recently, ACE outside-in signalling in endothelial cells has been described. The present study tested the hypothesis that ACE signalling is not restricted to endothelial cells and may act as an additional peptide receptor on human preadipocytes and adipocytes. ACE protein levels were not changed during adipose conversion of human primary preadipocytes. The enzyme was primarily localized to the non-detergent-resistant fraction of the membrane and phosphorylated in non-dividing cells. Antibody arrays of whole cell lysate detected putative ACE-interacting proteins, which all share important roles in cell cycle control and/or apoptosis. These findings suggest that ACE is a versatile molecule, involved both in the regulation of extracellular peptide concentrations and direct intracellular signalling. In human adipose cells ACE may potentially influence exit from the cell cycle, differentiation, and programmed cell death signalling.     

High risk of essential hypertension in males with intron 4 VNTR polymorphism of eNOS gene

In this study 250 patients with essential hypertension were investigated in comparison to 218 normotensives for association with epidemiological parameters. Of these DNA samples from 176 patients and 168 controls were analyzed for intron 4 27bp repeat polymorphism of eNOS gene. The study revealed significantly high risk of essential hypertension for individuals who were obese, with a positive family history and with non-vegetarian food habits. Though the intron 4b/a polymorphism of eNOS gene did not reveal any association with essential hypertension in general, males with a/a genotype of the polymorphism did show significantly high risk for developing hypertension.     

Ginkgo biloba extract for essential hypertension: A systemic review

BackgroundGinkgo biloba extract (GBE), a traditional natural herbal product, is often used in the treatment of essential hypertension (EH) as complementary therapy in China and European countries.AimTo critically assess the current clinical evidence of efficacy and safety of GBE for EH.Methods7 electronic databases (Cochrane Library, PubMed, EMBASE, VIP, CBM, Wanfang data, and CNKI) were searched to identify randomized controlled trials (RCTs) of GBE for EH. Methodological quality was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions.ResultsA total of 9 RCTs with 1012 hypertensive patients were identified and reviewed. Most RCTs were of high risk of bias with flawed study design and poor methodological quality. 6 trials demonstrated potential positive effect of GBE as complementary therapy on BP reduction when compared with antihypertensive drug therapy; however, it was not associated with a statistically significant effect on both SBP and DBP reduction in 3 other trials. Despite the positive findings, there were so many methodological limitations and significant clinical heterogeneity. Most of the trials did not report adverse effects, and the safety of GBE is still uncertain.ConclusionNo confirmative conclusions on the efficacy and safety of GBE for EH could be drawn. More rigorous trials are warranted to support their clinical use.     

Conjugated linoleic acid prevents the development of essential hypertension in spontaneously hypertensive rats

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid found in beef, lamb, and dairy products. CLA has attracted considerable attention over the past several decades because of its potentially beneficial biologic effects, including protective effects against several cancers, atherosclerosis, and obesity. In previous studies, we provided evidence that dietary CLA could prevent the development of obesity-related hypertension in obese animals. Here, we show that CLA suppresses the development of non-obese essential hypertension in spontaneously hypertensive rats (SHRs). After 4 weeks of feeding with CLA, the increase of systolic blood pressure was significantly suppressed compared with rats fed linoleic acid. Abdominal adipose tissue weight was also significantly lowered in CLA-fed SHRs. Content of arachidonic acid, the substrate of eicosanoid production, was not changed, but accumulation of oleic acid, the lipogenesis end-product, was markedly decreased in the membrane phospholipids of CLA-fed SHRs. In addition, we found increased level of plasma adiponectin, suggested as a regulatory factor of hypertension, through the enhancement of mRNA expression in CLA-fed SHRs. We speculate that the antihypertensive effect of dietary CLA may be due to the increase of plasma adiponectin level and associated with the alleviation of membrane abnormality in SHRs.     

Association of WNK1 exon 1 polymorphisms with essential hypertension in Hani and Yi minorities of China

The association of polymorphisms in exon 1 of the WNK1 gene with essential hypertension in the minority groups of Hani and Yi of China was investigated in the case-control study. The sequence of 1257 bp containing the WNK1 gene exon 1 was determined in 1307 individuals (649essential hypertension subjects and 658 controls) to identify SNPs in Hani and Yi minority groups. Four of eleven previously known SNPs (rs3168640, rs11885, rs11554421 and rs34880640) were identified. The SNP analysis indicated that SNPs rs11885 and rs11554421 were significantly associated with hypertension in both Hani and Yi populations, and rs34880640 was significantly associated with hypertension in Hani but not in Yi population, adjusted for covariates. Haplotype analysis indicated that the haplotype H1 significantly decreased the risk of hypertension in both populations. These results suggested that WNK1 polymorphisms were involved in the predisposition of essential hypertension in Hani and Yi populations and its effects showed a clear population specificity. This finding supported the importance of population specificity in determining the genetic factors associated with diseases and thus disease treatment.     

Angiotensin-converting enzyme gene polymorphism and allele frequencies in the lebanese population: prevalence and review of the literature

We studied the distribution of the D/D, I/D, and I/I genotypes of the angiotensin-converting enzyme (ACE) in a sample of healthy Lebanese individuals to assess their prevalence and compare them with other populations. ACE genotypes were determined using the Cardiovascular Disease (CVD) StripAssay, which is based on a Polymerase Chain Reaction-Reverse hybridization technique. DNA from 133 unrelated healthy donors from our HLA-bank was used. The prevalence of D/D, I/D, and I/I genotypes was found to be 39.1, 45.1, and 15.8% respectively, with D and I allelic frequency of 61.7 and 38.3%, respectively. The sampled Lebanese population showed ACE genotypic distributions similar to Caucasians; however, with tendency towards harboring high D allele frequency together with a low I allele frequency just like the Spanish population. This first report from Lebanon will serve as a baseline statistical data for future investigations of the prevalence of ACE genotypes in association with various clinical entities notably cardiovascular diseases. The medical literature was also reviewed in this context.     

Gly460Trp polymorphism of the ADD1 gene and essential hypertension in an Indian population: A meta-analysis on hypertension risk

BACKGROUND:

Essential hypertension is a complex genetic trait. Genetic variant of alpha adducin (ADD1) gene have been implicated as a risk factor for hypertension. Given its clinical significance, we investigated the association between ADD1 Gly460Trp gene polymorphism and essential hypertension in an Indian population. Further, a meta-analysis was carried out to estimate the risk of hypertension.

METHODS:

In the current study, 432 hypertensive cases and 461 healthy controls were genotyped for the Gly460Trp ADD1 gene polymorphism. Genotyping was determined by real time PCR using Taqman assay. Multiple logistic regression analysis was used to detect the association between Gly460Trp polymorphism and hypertension.

RESULTS:

No significant association was found in the genotype and allele distribution of Gly460Trp polymorphism with hypertension in our study. A total of 15 case-control studies were included in the meta-analysis. There was no evidence of the association of Gly460Trp polymorphism with hypertension in general or in any of the sub group.

CONCLUSIONS:

We found that the Gly460Trp polymorphism is not a risk factor for essential hypertension in a south Indian Tamilian population. However, the role of ADD1 polymorphism may not be excluded by a negative association study. Further, large and rigorous case-control studies that investigate gene–gene–environment interactions may generate more conclusive claims about the molecular genetics of hypertension.     

Risk conferred by FokI polymorphism of vitamin D receptor (VDR) gene for essential hypertension

BACKGROUND:

The vitamin D receptor (VDR) gene serves as a good candidate gene for susceptibility to several diseases. The gene has a critical role in regulating the renin-angiotensin system (RAS) influencing the regulation of blood pressure. Hence determining the association of VDR polymorphisms with essential hypertension is expected to help in the evaluation of risk for the condition.

AIM:

The aim of this study was to evaluate association between VDRFok I polymorphism and genetic susceptibility to essential hypertension.

MATERIALS AND METHODS:

Two hundred and eighty clinically diagnosed hypertensive patients and 200 normotensive healthy controls were analyzed for Fok I (T/C) [rs2228570] polymorphism by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Genotype distribution and allele frequencies in patients and controls, and odds ratios (ORs) were calculated to predict the risk for developing hypertension by the individuals of different genotypes.

RESULTS:

The genotype distribution and allele frequencies of Fok I (T/C) [rs2228570] VDR polymorphism differed significantly between patients and controls (χ² of 18.0; 2 degrees of freedom; P = 0.000). FF genotype and allele F were at significantly greater risk for developing hypertension and the risk was elevated for both the sexes, cases with positive family history and habit of smoking.

CONCLUSIONS:

Our data suggest that VDR gene Fok I polymorphism is associated with the risk of developing essential hypertension     

Oxygen free radicals in essential hypertension

Membrane abnormalities in essential hypertensives (EH) are well known. The respiratory burst enzyme, NADPH oxidase is located in the cell membrane of the neutrophil (PMNLs) and its activity is important in generation of oxygen derived free radical (OFR). Recently OFR have been implicated in vascular changes in variety of conditions. An attempt was made to delineate the status of OFR and antioxidants in EH. Ten, age and sex-matched, healthy controls (GpI) and 26 untreated EH (Gp IIA mild-8, Gp IIB Moderate-8, Gp IIC Severe-10) were studied. After clinical examination and basic laboratory evaluation of subjects, neutrophils isolated from their blood were studied. Chemiluminescence (CL) emitted by PMNLs after stimulation was measured (counts/min) in a luminometer and was taken as measure of OFR production and thereby of NADPH oxidase activity. The levels of antioxidants, super oxide dismutase (SOD) and reduced glutathione (GSH), were also estimated. Chemiluminescence was increased significantly (p < 0.01) in Gp IIC (243.04 ± 24.9 × 10³ counts per minute) as compared to Gp IIA (2.80 ± 1.87), Gp IIB (34.54 ± 30.24) and Gp I (0.52 ± 0.15) and SOD was reduced significantly (p < 0.05) in all EH (Gp IIA 3.9 ± 0.3 units per mg protein, Gp IIB 3.5 ± 0.3 and Gp IIC 3.12 ± 0.3) as compared to controls (4.1 ± 0.2). Similarly GSH was reduced (p < 0.05) in EH (Gp IIA 11.2 ± 1.7 mg per gm protein, Gp IIB 8.5 ± 1.1 and Gp IIC 6.6 ± 0.3) as compared to Gp I (13.5 ± 2.5). In essential hypertensives a curvilinear positive correlation was obtained between CL and both systolic (r = 0.7077, p < 0.01) and diastolic (r = 0.7965, p < 0.01) blood pressure. A significant inverse correlation (p < 0.05) was obtained between systolic and diastolic blood pressure on one hand and GSH and SOD on the other. Thus PMNLs of EH have increased emission of CL and depletion of antioxidants. The results indicate that in essential hypertension increased membrane NADPH oxidase activity is present.Abbreviations EH Essential Hypertensives - PMNLs Polymorphonuclear leucocytes - OFR Oxygen derived free radicals - Gp Group - NADPH Reduced Nicotinamide Adenine Dinucleotide Phosphate - CL Chemiluminescence - SOD Superoxide Dismutase - GSH Reduced Glutathione - SBP Systolic blood pressure - DBP Diastolic blood pressure     

The 1.3 A resolution structure of the RNA tridecamer r(GCGUUUGAAACGC): metal ion binding correlates with base unstacking and groove contraction

Metal ions play a key role in RNA folding and activity. Elucidating the rules that govern the binding of metal ions is therefore an essential step for better understanding the RNA functions. High-resolution data are a prerequisite for a detailed structural analysis of ion binding on RNA and, in particular, the observation of monovalent cations. Here, the high-resolution crystal structures of the tridecamer duplex r(GCGUUUGAAACGC) crystallized under different conditions provides new structural insights on ion binding on GAAA/UUU sequences that exhibit both unusual structural and functional properties in RNA. The present study extends the repertory of RNA ion binding sites in showing that the two first bases of UUU triplets constitute a specific site for sodium ions. A striking asymmetric pattern of metal ion binding in the two equivalent halves of the palindromic sequence demonstrates that sequence and its environment act together to bind metal ions. A highly ionophilic half that binds six metal ions allows, for the first time, the observation of a disodium cluster in RNA. The comparison of the equivalent halves of the duplex provides experimental evidences that ion binding correlates with structural alterations and groove contraction.     

Association of insertion/deletion polymorphism of alpha-adrenoceptor gene in essential hypertension with or without type 2 diabetes mellitus in Malaysian subjects

An insertion/deletion (I/D) polymorphism of Alpha2B-Adrenoceptor (ADRA2B) gene located on chromosome 2 has been studied extensively in related to cardiovascular diseases. The main aim of the present study was to examine the potential association of D allele frequency of I/D polymorphism of ADRA2B gene in Malaysian essential hypertensive subjects with or without type 2 diabetes mellitus (T2DM). This study includes 70 hypertensive subjects without T2DM, 65 hypertensive subjects with T2DM and 75 healthy volunteers as control subjects. Genotyping of I/D polymorphism was performed by conventional PCR method. There was significant difference found in age, body mass index, systolic/diastolic blood pressure and high density lipoprotein cholesterol level between the case and control subjects. DD genotypic frequency of I/D polymorphism was significantly higher in hypertensive subjects (42.84% vs. 29.33%; P-=0.029) and in hypertensive with T2DM subjects (46.15% vs. 29.33%; P=0.046) than control group. D allele frequency was higher in hypertensive group (67.41%) than control subjects (52.67%). However, no significant difference was found between the three genotypes of I/D polymorphism of ADRA2B gene and the clinical characteristics of the subjects. The result obtained in this study show D allele of ADRA2B gene was associated with essential hypertension with or without T2DM in Malaysian subjects.     

Mineral Factors Controlling Essential Hypertension—a Study in the Chandigarh, India Population

Essential hypertension (EH) is a major public health problem world over and in India. Recent data on EH in the population of Chandigarh (Union Territory and capital of Punjab and Haryana States of India) revealed that the prevalence of EH has become double in the last 30 years in the residents of Chandigarh (26.9 to 45.80% in the year 1968 and 2002). Zinc (Zn), copper (Cu), magnesium (Mg), and manganese (Mn) in the serum are considered important in maintaining the human hypertension. The high Zn intake was considered to increase the blood pressure (BP) and to affect the other mineral status in the body. Recent survey on the trace metal status of different vegetables in the State of Punjab around Chandigarh (India) revealed that Zn level is significantly higher (40 mg/kg or more in above ground vegetables and 120 mg/kg or above in underground vegetables) in underground water-irrigated vegetables, but the levels of Cu and Mg are within prescribed limit. The present study was conducted on Chandigarh population to evaluate the levels of Zn, Cu, Mg, and Mn in the blood and urine of normotensive (NT) control and hypertensive (HT) subjects matched with number, age and sex. Atomic absorption spectrophotometer studies revaluated that the levels of serum Zn, Mg, and Mn were significantly higher (p < 0.001), but the level of Cu was low in the HT subjects (BP = 160/93) compared to NT control (BP = 140/83). Higher levels of urinary Zn, Cu, Mg, and Mn were observed in the HT subject vs NT control (p < 0.001). Positive correlations were evaluated between the levels of serum Zn, Mg, and Mn vs systolic and diastolic pressures (DP and SP), respectively (r = 0.928, 0.863, 0.876, 0.808, 0.404, 0.326, p < 0.01), but negative and positive nonsignificant correlations between the serum Cu with SP and DP were recorded (r = −0.032, r = 0.024). Positive correlations were also evaluated between urinary levels of Zn, Cu, Mg, and Mn vs SP and DP (r = 0.718, 0.657, 0.750, 0.681, 0.630, 0.578, 0.516, 0.461, p < 0.01). Prevalence of essential hypertension may be due to higher Zn level in the food chain that makes the individuals vulnerable to other diseases over the time related to essential hypertension.     

Augmentation of microsporidia adherence and host cell infection by divalent cations

The infection process of intracellular opportunistic microsporidia involves the forcible eversion of a coiled hollow polar filament that pierces the host cell membrane, allowing the passage of infectious sporoplasm into the host cell cytoplasm. Although the exact mechanism of spore activation leading to polar filament discharge is unknown, we have shown that spore adherence to host cells, which is mediated by sulfated glycosaminoglycans, may play a vital role. When adherence is inhibited, host cell infection decreases, indicating a direct link between adherence and infection. The goal of this study was to evaluate the effects of exogenous divalent cations on microsporidia spore adherence and infection. Data generated using an in vitro spore adherence assay show that spore adherence is augmented by manganese (Mn2+) and magnesium (Mg2+), but not by calcium (Ca2+). However, each of the three divalent cations contributed to increased host cell infection when included in the assay. Finally, we show that Mn2+ and Mg2+ may activate a constituent on the microsporidia spore, not on the host cell, leading to higher infection efficiency. This report further supports recent evidence that spore adherence to the host cell surface is an important aspect of the microsporidial infection process.     

Compartmentation of newly synthesized phosphatidylethanolamine in rat brain microsomes

Summary The compartmentation of the phosphatidylethanolamine newly synthesized in brain microsomesin vitro either by base exchange or net synthesis has been studied, using difluorodinitrobenzene as a chemical probe. The experimental results demonstrate that in rat brain microsomes the phosphatidylethanolamine molecules synthesized by base exchange and the bulk membrane lipid belong to different pools. Ca²⁺ bound to microsomes seems to be involved in the maintenance of the compartmentation of phosphatidylethanolamine. In the presence of Ca²⁺ the newly synthesized phosphatidylethanolamine molecules react with difluorodinitrobenzene as though they are organized in clusters. After biosynthesisin vivo orin vitro through the cytidine pathway, the compartmentation of the newly formed phosphatidylethanolamine appears less marked than after the synthesis through base exchange.     

瑞舒伐他汀对高血压合并高胆固醇血症患者血清高敏C 反应蛋白水平的影响*

摘要目的：观察瑞舒伐他汀对高血压合并高胆固醇血症患者血清高敏C 反应蛋白(hi-sensitive C-reactive protein,hs-CRP)水平的 影响。方法：选择60 例高血压合并高胆固醇血症的患者为研究对象,将其随机分为瑞舒伐他汀治疗组(实验组)和常规方法治疗组 (对照组),对照组仅给予常规治疗,实验组在常规组治疗的基础上每日加服一次瑞舒伐他汀10mg,疗程8 周,测定和比较两组患 者治疗前后血压、血清总胆固醇(Total cholesterol,TC)、低密度脂蛋白胆固醇(Low density lipoprotein-cholesterol,LDL-C)和hs-CRP 的水平。结果：治疗8 周后,实验组患者的血清SBP、DBP、TC、LDL-C、hs-CRP水平均较治疗前明显降低(P<0.05),且较对照组组更 低(P<0.05)。结论：瑞舒伐他汀辅助治疗能显著降低高血压合并高胆固醇血症患者的血压和血清血脂水平,并可减少血清高敏C 反应蛋白水平,有益于改善患者的预后。     

Serotype‐dependent expression patterns of stabilized lipopolysaccharide aggregates in Aggregatibacter actinomycetemcomitans strains

Above a critical concentration, amphiphilic lipopolysaccharide (LPS) molecules in an aqueous environment form aggregate structures, probably because of interactions involving hydrophobic bonds. Ionic bonds involving divalent cations stabilize these aggregate structures, making them resistant to breakdown by detergents. The aim of this study was to examine expression patterns of stabilized LPS aggregates in Aggregatibacter actinomycetemcomitans, a microorganism that causes periodontitis. A. actinomycetemcomitans strains of various serotypes and truncated LPS mutants were prepared for this study. Following treatment with a two‐phase separation system using the detergent Triton X‐114, crude LPS extracts of the study strains were separated into detergent‐phase LPS (DP‐LPS) and aqueous‐phase LPS (AP‐LPS). Repeated treatment of the aqueous phase with the two‐phase separation system produced only a slight decrease in AP‐LPS, suggesting that AP‐LPS was resistant to the detergent and thus distinguishable from DP‐LPS. The presence of divalent cations increased the yield of AP‐LPS. AP‐LPS expression patterns were serotype‐dependent; serotypes b and f showing early expression, and serotypes a and c late expression. In addition, highly truncated LPS from a waaD (rfaD) mutant were unable to generate AP‐LPS, suggesting involvement of the LPS structure in the generation of AP‐LPS. The two‐phase separation was able to distinguish two types of LPS with different physical states at the supramolecular structure level. Hence, AP‐LPS likely represents stabilized LPS aggregates, whereas DP‐LPS might be derived from non‐stabilized aggregates. Furthermore, time‐dependent expression of stabilized LPS aggregates was found to be serotype‐dependent in A. actinomycetemcomitans.     

整合蛋白与抑制剂设计

整合蛋白是一类重要的细胞表面黏附分子,由α和β亚基以非共价键结合而形成的异二聚体糖蛋白,对免疫反应、免疫细胞的组织定位、凝血、组织愈伤、癌细胞转移和新血管生成以及骨重塑等都至关重要。整合蛋白的功能依赖于对其配体结合的亲和性,以及所介导的下游信号通路。目前,对整合蛋白构象调节及亲和力调控机制已有深入了解。人类24种整合蛋白中,已有3种整合蛋白作为临床治疗靶点。这些药物以单克隆抗体、多肽和小分子化合物为主,均针对配体识别序列而设计。该类抑制剂往往具有部分激活的作用,直接导致药物的副反应和毒性。为了改善第一代整合蛋白药物的不足,目前基于晶体结构研究、虚拟筛选、高通量筛选以及基于结构设计的新型整合蛋白抑制剂,已经有许多进入临床试验。本文综述了一系列晶体结构中蛋白质与抑制剂的相互作用,以及借助晶体结构获得纯抑制剂为目的的实例,这些策略将会对开发新型有效的整合蛋白抑制剂提供很好的参考。