Physiologic and molecular consequences of endothelial Bmpr2 mutation

Background

Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown.

Methods

In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2^delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2^delx4+ or Bmpr2^R899X mutation.

Results

Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2^delx4+ and Bmpr2^R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2^delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2^R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells.

Conclusions

Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis.     

不同年龄自发性高血压大鼠心脏AT2R的表达与心肌纤维化

目的观察不同年龄自发性高血压大鼠（SHR）心脏AT2R的表达水平及心肌胶原含量,探讨AT2R在高血压发生、发展过程中的作用。方法 1月龄组（S1）、2月龄组（S2）、3月龄组（S3）、6月龄组（S6）和9月龄组（S9）雄性SHR共五组,每组各6只,各组均有相应月龄的Wistar-Kyoto大鼠（WKY）作对照。采用RBP-I型大鼠血压心率测定仪测量大鼠动脉收缩压（SBP）;放免法（RIA）测定血浆血管紧张素Ⅱ（AngⅡ）;免疫组化染色结合计算机图像分析方法测定心脏AT2R的表达水平,天狼星红胶原染色大鼠的心脏切片。结果 1.SHR SBP随着月龄的增加呈持续上升（P〈0.05）,SHR的SBP均高于相应配对的WKY组（P〈0.05）。2.一个月后SHR血浆AngⅡ浓度均高于S1（P〈0.05）,一个月后SHR血浆AngⅡ浓度均高于相应配对的WKY组（P〈0.05）。3.SHR心脏AT2R免疫染色阳性面积比随着月份的增加而降低,SHR心脏AT2R免疫染色阳性面积比均低于相应配对的WKY组（P﹤0.05）4.SHR心肌中的胶原含量随着月龄的增加而增加。结论 SHR心脏AT2R表达水平比WKY低,并随着年龄的增加而降低。SHR心肌中的胶原含量随着月龄的增加而增加,而WKY无类似趋势。     

Analysis of mitochondrial genome revealed a rare 50 bp deletion and substitutions in a family with hypertension

We have sequenced the complete mtDNA of a family with hypertension (HT), type 2 diabetes (T2D) and coronary artery disease (CAD). Our analysis revealed two novel mutations (C3519T, G13204A); of which G13204A replaces valine to isoleucine. In silico analysis of a rare missense mutation (T8597C) showed a deleterious effect. We also observed a 50 bp deletion (m.298_347del50) in the hypervariable region II (HVSII) of all the individuals, who had a common maternal lineage. This (50 bp) deletion was not found in 17,785 individuals from different ethnic populations of India or in a variety of different disease phenotypes. We predict that the mtDNA mutations might be responsible for the HT. Analysis of POLG (polymerase gamma) gene revealed 14 variants which might be responsible for some of the mtDNA mutations seen in this family.     

高血压病患者健康教育干预探讨以及效果分析

目的：观察健康教育对原发性高血压病人的干预效果。方法：将80例原发性高血压患者随机分为两组,观察组用药物治疗的同时配合健康教育;对照组单纯药物治疗。观察两组患者治疗前后血压及生活行为的改变情况,进行比较分析。结果：观察组降压效果明显优于对照组（P〈0．01）;两组患者行为模式转变具有显著性差异（P〈0．01）。结论：综合运用药物治疗和健康教育,能消除或减轻危险因素的作用,使高血压得到有效控制,以推迟或防止心脑血管病并发症的发生,提高患者的生活质量。     

不同时间服用比索洛尔对非杓犁高衄压缸压的影响

目的：观察不同给药时间分别给予比索洛尔对非杓型原发性高血压患者的降压疗效和血压节律恢复的影响。方法：选取60例非杓型高血压患者,采取随机平行对照试验,观察比索洛尔（n=30）每日早晨（8：00）给药2．5—10mg、比索洛尔（n=30）每日夜间（20：00）给药2．5—10mg治疗8周后的降压疗效。结果：两种给药方法均能降低非杓型高血压患者的全天血压（P〈0．05）。两种给药方法在白天的血压控制上无显著性差异（P〉0．05）,但在夜间血压的控制上夜间服药降压效果具有显著性差异（P〈0．05）。夜间服药在血压节律恢复方面优于早晨服药（P〈0．05）,早晨服药组有10例恢复杓型,夜间服药组有19例恢复杓型。结论：比索洛尔的两种给药方式均能安全有效的降压,但对于非杓型高血压患者夜间服药优于早晨服药,更有利于血压节律的恢复。     

升温诱发高血压大鼠脑梗塞发病的神经内分泌机制

目的:研究气温骤升导致高血压大鼠发生脑梗塞的神经内分泌机制。方法:采用易卒中型肾血管性高血压(RHRSP)模型,放置于人工模拟气温骤升的高温环境中诱发脑梗塞,检测高温刺激前后大鼠ACTH、CORT、TSH、T3、T4的变化。结果:突然升温使生理组大鼠ACTH和CORT水平表现升高的趋势。模型组高血压大鼠CORT、TSH、T3、T4水平在升温中均呈现升高趋势,但是ACTH水平却明显降低(P<0.05)。升温后发生脑梗塞大鼠的ACTH和T4水平与升温前比明显下降(P<0.01),而TSH水平明显高于升温前水平(P<0.05),T3水平不变。结论:高血压机体应激反应系统紊乱,甲状腺刺激素和肾上腺皮质激素的异常波动,是突然高温促发高血压机体脑梗塞发病的重要神经内分泌机制。     

阿托伐他汀治疗高血压并颈动脉粥样硬化的临床疗效观察

目的:观察阿托伐他汀治疗高血压并颈动脉粥样硬化的临床疗效。方法:选择高血压并颈动脉粥样硬化患者64例,按照自愿的原则分为对照组和观察组,对照组给予常规治疗,观察组在常规治疗的基础上给以阿托伐他汀治疗。治疗6个月后,比较两组患者血压、血脂及颈动脉斑块分级情况。结果:治疗6周后,两组患者在上述方面比较,差异均具有统计学意义,观察组优于对照组。结论:在高血压并颈动脉粥样硬化患者药物治疗过程中,应加行阿托伐他汀治疗,可提高临床疗效。     

Epoxyeicosatrienoic Acids (EETs) Regulate Epithelial Sodium Channel Activity by Extracellular Signal-regulated Kinase 1/2 (ERK1/2)-mediated Phosphorylation

The epithelial sodium channel (ENaC) participates in the regulation of plasma sodium and volume, and gain of function mutations in the human channel cause salt-sensitive hypertension. Roles for the arachidonic acid epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), in ENaC activity have been identified; however, their mechanisms of action remain unknown. In polarized M1 cells, 14,15-EET inhibited amiloride-sensitive apical to basolateral sodium transport as effectively as epidermal growth factor (EGF). The EET effects were associated with increased threonine phosphorylation of the ENaC β and γ subunits and abolished by inhibitors of (a) mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal regulated kinases 1 and 2 (MEK/ERK1/2) and (b) EGF receptor signaling. CYP2C44 epoxygenase knockdown blunted the sodium transport effects of EGF, and its 14,15-EET metabolite rescued the knockdown phenotype. The relevance of these findings is indicated by (a) the hypertension that results in mice administered cetuximab, an inhibitor of EGF receptor binding, and (b) immunological data showing an association between the pressure effects of cetuximab and reductions in ENaCγ phosphorylation. These studies (a) identify an ERK1/2-dependent mechanism for ENaC inhibition by 14,15-EET, (b) point to ENaC as a proximal target for EET-activated ERK1/2 mitogenic kinases, (c) characterize a mechanistic commonality between EGF and epoxygenase metabolites as ENaC inhibitors, and (d) suggest a CYP2C epoxygenase-mediated pathway for the regulation of distal sodium transport.     

Metabolic Syndrome in Permanent Night Workers

Night and shift work might be risk factors for metabolic and cardiovascular disorders due to interference with diet, circadian metabolic rhythms, and lifestyle. The relationship between permanent night work and metabolic and cardiovascular risk factors was explored in a retrospective longitudinal study of workers employed in a large municipal enterprise in charge of street cleaning and domestic waste collection. All subjects who had worked night shifts between 1976 and 2007 as hand sweepers, motor sweepers, and delivery tricar drivers were compared with subjects who always worked the same jobs but on day shifts. From the periodical medical surveillance files, we identified 488 male workers who had been examined on average five times (minimum 2, maximum 14) during the study period, for a total of 2,328 medical examinations; 157 always had worked day shifts, 12 always the night shift, and 319 both (initially day and subsequently night shifts). Their age ranged from 22 to 62 yrs, and work experience varied from 1 to 28 yrs. Lifestyle habits (smoking, alcohol consumption), body mass index, serum glucose, total cholesterol, tryglicerides, hepatic enzymes, blood pressure, resting electrocardiogram, diabetes, coronary heart disease, hypertension, and related drugs were taken into consideration for the analysis. We used generalized estimating equations (GEE) models (exchangeable correlation matrix) to analyze the relationship between night work and health effects while accounting for within‐subject correlations and adjusting for study period, job, age, and lifestyle variables. As a whole, night workers smoked more and had significantly higher BMI, serum total cholesterol, and triglycerides than day workers. Both the inter‐individual comparison between day and night workers and the intra‐individual comparison among the workers, who were day workers at the beginning of their employment and later became night workers, showed a significant increase in BMI, total cholesterol, and tryglicerides associated with night work. No consistent effect was seen on fasting glucose, hepatic enzymes, and blood pressure, whereas a higher incidence of coronary heart disease was recorded in night workers.