血管紧张素转换酶2-血管紧张素1-7-Mas轴对血管作用的研究进展

血管紧张素转换酶2（ACE2）和Mas受体的发现使人们对肾素-血管紧张素（RAS）有了更全面的认识。ACE2可水解血管紧张素Ⅰ和血管紧张素Ⅱ直接或间接生成血管紧张素1-7（Ang 1-7）,并与高血压的形成密切相关。Ang 1-7主要通过Mas受体引起血管舒张、抑制细胞增殖。ACE2-Ang1-7-Mas轴的发现为RAS的研究、高血压等心血管疾病的防治和新药开发提供了新的思路和方向。     

血管紧张素II2型受体基因缺失不影响肾素—血管紧张素系统

基于目前对血管紧张素Ⅱ２型受体（ＡＴ２）功能的认识,认为血管紧张素Ⅱ１型受体（ＡＴ１）和ＡＴ２受体有相互拮抗作用。依据上述论点,本研究利用ＡＴ２受体基因敲出小鼠,观察了ＡＴ２受体缺失后是否造成肾素－血管紧张素系统其它成分代偿性紊乱。结果发现,ＡＴ２受体基因缺失小鼠血浆和肾组织中血管紧张素Ⅱ的浓度以及肾组织中肾素、ＡＴ１Ａ受体的基因表达均未发生明显改变,表明ＡＴ２受体缺失未对肾素－血管紧张素系统产生     

血管紧张素受体1在血管紧张素Ⅱ诱导人星形胶质细胞老化中的作用

目的通过体外细胞实验研究,探讨血管紧张素受体1在血管紧张素Ⅱ诱导人星形胶质细胞活性氧产生和细胞老化中的作用。方法人星形胶质细胞随机分为三组：血管紧张素Ⅱ＋Cand（坎地沙坦）组和血管紧张素Ⅱ＋tempol组。血管紧张素Ⅱ组是用100nM血管紧张素Ⅱ刺激人星形胶质细胞3天,血管紧张素Ⅱ＋Cand组和血管紧张素Ⅱ＋tempol组先用血管紧张素受体1阻滞剂坎地沙坦（100nM）和氧自由基清除剂tempol（3mM）预处理,再用100nM血管紧张素II刺激人星形胶质细胞3天,利用β半乳糖苷酶染色评估细胞老化。不同剂量（0、1nM、10nM、100nM、1000nM和1000nM＋坎地沙坦）的血管紧张素Ⅱ刺激人星形胶质细胞30min,DHE染色评估细胞内活性氧产生。结果血管紧张素Ⅱ引起人星形胶质细胞DHE染色表达增多和β半乳糖苷酶染色细胞增多。利用血管紧张素受体1阻滞剂坎地沙坦和氧自由基清除剂tempol预处理逆转了血管紧张素Ⅱ引起的星形胶质细胞老化。结论血紧张素Ⅱ是通过血管紧张素受体1和超氧阴离子产生引起星形胶质细胞的老化。     

血管紧张素Ⅱ诱导左心室原癌基因c—fos和c—myc的表达

本实验用Ｌａｎｇｅｎｄｏｒｆｆ心脏灌流装置,探讨血管紧张素Ⅱ对左心室原癌基因ｃ－ｆｏｓ和ｃ－ｍｙｃ表达的作用。观察到血管紧张素Ⅱ能诱导左心室ｃ－ｆｏｓ和ｃ－ｍｙｃ的表达,ｃ－ｆｏｓ表达早于ｃ－ｍｙｃ表达,并呈量－效关系。这种作用可被血管紧张素Ⅱ受体抗剂ｓａｒａｌａｓｉｎ所阻断。这些结果提示血管紧张素Ⅱ诱导的ｃ－ｆｏｓ和ｃ－ｍｙｃ的表达是受体介导的。ＴＴＳ完全阻断血管紧张素Ⅱ诱导的ｃ－ｆｏｓ表达。     

内皮细胞血管紧张素Ⅱ信号转导通路的研究进展

血管紧张素Ⅱ(Ang Ⅱ)不仅发挥着收缩血管和调节血压的功能,还参与炎症、内皮细胞功能障碍、动脉粥样硬化、高血压和充血性心衰的发生与发展.Ang Ⅱ通过AT1受体,激活内皮细胞MAPK、NADPH和ROS、非受体酪氨酸激酶及受体酪氨酸激酶通路产生各种生物学效应,参与内皮细胞功能调节,引发内皮细胞功能障碍和血管的炎症反应.     

子宫-胎盘血管紧张素及其受体

子宫－胎盘中存在局部肾素－血管紧张素系统（ｒｅｎｉｎ－ａｎｇｉｏｔｅｎｓｉｎ ｓｙｓｔｅｍ,ＲＡＳ）。血管紧张素的分布较广泛,胎盘合体滋养层、子宫腺体、肌肉和血管壁均可见ＡｎｇⅡ的免疫阳性染色。胎盘主要表达血管紧张素Ⅰ型受体,子宫至少有两种血管紧张素受体亚型,其分布与数量存在种间差异。血管紧张素Ⅰ型受体与Ｇ蛋白偶联,可以激活三种不同的信号途径,Ⅱ型受体能否与Ｇ蛋白偶联及其信号转导途径仍有不同看法。     

血管紧张素Ⅱ2型受体基因缺失不影响肾素-血管紧张素系统

基于目前对血管紧张素Ⅱ2型受体(AT2)功能的认识,认为血管紧张素Ⅱ1型受体(AT1)和AT2受体有相互拮抗作用.依据上述论点,本研究利用AT2受体基因敲出小鼠,观察了AT2受体缺失后是否造成肾素-血管紧张素系统其它成分代偿性紊乱.结果发现,AT2受体基因缺失小鼠血浆和肾组织中血管紧张素Ⅱ的浓度以及肾组织中肾素、AT1A受体的基因表达均未发生明显改变,表明AT2受体缺失未对肾素-血管紧张素系统产生显著影响,AT2受体的功能已被代偿,但代偿途径尚有待于进一步研究.     

血管紧张素Ⅱ对氧化低密度脂蛋白受体LOX1基因表达的调控

目的：观察不同浓度血管紧张素Ⅱ对氧化低密度脂蛋白内皮受体LOX1基因表达的影响,并探讨其机制。方法：采用反转录-聚合酶链反应（RT PCR）。结果：（1）血管紧张素Ⅱ可上调LOXI的mRNA水平,且呈剂量依赖效应;（2）应用血行之有效紧张素Ⅱ一型受体阻断齑osartan后抑制了血紧张素Ⅱ对LOX1的上调作用。结论：血管紧张素Ⅱ可显著上调LOX1的基因表达,且呈剂量依赖效应。这一作用是通过激活血管紧张素Ⅱ一型受体发生的。     

肾素 - 血管紧张素 - 醛固酮系统阻滞的研究进展

肾素-血管紧张素-醛固酮系统起初被认为是较简单的神经体液调节机制之一。但是,这一想法随着RAAS阻滞剂:肾素阻滞剂、血管紧张素转换酶抑制剂(ACEI)、AT1受体拮抗剂及盐皮质激素受体拮抗剂的深入研究而受到挑战。因此,RAAS的组成、以上药物发挥作用的具体通路及副作用均得到重新定义。在RAAS阻滞剂的应用过程中,机体肾素水平升高,并刺激肾素原受体(即无活性的肾素前体,PRR),进而对机体造成不良影响。同理,在AT1受体拮抗剂的应用过程中,血浆血管紧张素II的水平升高,并与2型血管紧张素II(AT2)受体结合,进而对机体产生有利作用。此外,随着ACEI及ARB的应用,血管紧张素1-7水平升高,其与Mas受体结合,发挥心脏及肾脏保护的作用,还可通过刺激干细胞发挥组织修复作用。     

RAAS与肝纤维化的研究进展

肝纤维化是多种慢性肝病进展至肝硬化的中间过程,其特征是以胶原蛋白为主的细胞外基质(extracellular matrix,ECM)的合成与降解失衡,导致大量ECM沉积。在肝纤维化发生、发展过程中,常伴有肾素–血管紧张素–醛固酮系统(renin-angiontensin-aldosterone system,RAAS)的激活,血管紧张素转换酶–血管紧张素II-血管紧张素II受体1(angiotensin-converting enzymeangiotensin IIangiotensin II type 1 repector,ACE-Ang II-AT1R)轴和血管紧张素转换酶2-血管紧张素(1-7)-Mas受体[angiotensin-converting enzyme 2-angiotensin(1-7)-Mas,ACE2-Ang(1-7)-Mas]轴是调节肝纤维化的两大重要因素。     

Renin-angiotensin system inhibition on noradrenergic nerve terminal function in pacing-induced heart failure

Chronic angiotensin-converting enzyme (ACE) inhibition has been shown to improve cardiac sympathetic nerve terminal function in heart failure. To determine whether similar effects could be produced by angiotensin II AT(1) receptor blockade, we administered the ACE inhibitor quinapril, angiotensin II AT(1) receptor blocker losartan, or both agents together, to rabbits with pacing-induced heart failure. Chronic rapid pacing produced left ventricular dilation and decline of fractional shortening, increased plasma norepinephrine (NE), and caused reductions of myocardial NE uptake activity, NE histofluorescence profile, and tyrosine hydroxylase immunostained profile. Administration of quinapril or losartan retarded the progression of left ventricular dysfunction and attenuated cardiac sympathetic nerve terminal abnormalities in heart failure. Quinapril and losartan together produced greater effects than either agent alone. The effect of renin-angiotensin system inhibition on improvement of left ventricular function and remodeling, however, was not sustained. Our results suggest that the effects of ACE inhibitors are mediated via the reduction of angiotensin II and that angiotensin II plays a pivotal role in modulating cardiac sympathetic nerve terminal function during development of heart failure. The combined effect of ACE inhibition and angiotensin II AT(1) receptor blockade on cardiac sympathetic nerve terminal dysfunction may contribute to the beneficial effects on cardiac function in heart failure.     

ELITE II and Val-HeFT are different trials: together what do they tell us?

The Losartan Heart Failure Survival Study (ELITE II) and the Valsartan Heart Failure Trial (Val-HeFT) both evaluated the efficacy and tolerability of a selective angiotensin II receptor antagonist on morbidity and mortality in patients with symptomatic heart failure. The trials differed, however, in terms of their primary hypothesis, study design, and treatment regimens, and this must be taken into consideration when comparing and interpreting the data from these studies. The data are in many ways complementary, and add to our understanding of the optimal treatment of symptomatic heart failure. Additional studies are needed, however, to fully define the role of angiotensin II receptor antagonists in the management of this very heterogeneous group of patients.     

Heart failure and angiotensin converting enzyme inhibition: problems and perspectives.

Heart failure has become the most widely studied syndrome in cardiology over the recent years. Despite the encouraging achievements by angiotensin converting enzyme (ACE) inhibitors, the mortality of patients with chronic heart failure remains high. There are several factors which can potentially be responsible for the fact that about 80% of patients with a failing heart defy protection by ACE inhibitors: different activation of tissue and systemic renin-angiotensin system (RAS) in a particular heart disease and the distinct ability of various ACE inhibitors to block cardiac ACE, alternative pathways for angiotensin II formation (chymase), genetic polymorphism of the RAS system and the complexity of neuroendocrine activation. Moreover, chronic heart failure can provoke disturbances in the reactivity of peripheral vessels and metabolism of striated muscles. These factors may then potentiate the vicious circle of heart failure. New therapeutic approaches, which could further reduce the mortality in patients with heart failure involve angiotensin II type 1 receptor antagonists, beta-blockers, aldosterone antagonists and blockers of the endothelin receptor. A number of questions associated with functions of the RAS still remain open and their solution could be of substantial benefit for patients with a failing heart.     

Metabolic modulation and cellular therapy of cardiac dysfunction and failure

At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.     

黄芪注射液联合米力农治疗充血性心力衰竭的临床分析

目的:观察黄芪注射液联合米力农治疗充血性心力衰竭的临床疗效及安全性.方法:将76例充血性心力衰竭患者随机分成两组,其中治疗组38人,对照组38人.所有患者均采取使用利尿剂、口服血管紧张素转换酶抑制药等常规治疗,治疗组患者在常规治疗基础上采用米力农联合黄芪注射液治疗,对照组患者在常规治疗基础上采用米力农治疗,从临床疗效、心衰疗效计分、心率、心脏指数、心输出量及左心室射血分数指标进行评价.结果:治疗组的临床疗效、心衰疗效计分、心率、左心室射血分数与对照组相比,有统计学差异(P＜0.05).结论:黄芪注射液联合米力农治疗充血性心力衰竭的临床疗效优于单纯应用米力农.     

Human adipose tissue cells keep tight control on the angiotensin II levels in their vicinity

Human adipose tissue expresses all components necessary for the local production of angiotensin II, which has multiple functions in adipose tissue, ranging from regulation of local blood flow to complex influences on tissue homeostasis. Still the mechanisms controlling human adipose tissue angiotensin II concentrations are not yet known. We investigated whether angiotensin II is degraded by human primary cultured preadipocytes and adipocytes and which enzymes are responsible for its metabolism. Distinct but transient angiotensin II production was limited by degradation due to consecutive proteolytic cleavage by endopeptidase and aminopeptidase activities. The endopeptidase could be identified as neprilysin expressed on the surface of both preadipocytes and adipocytes. Degradation of angiotensin II was preceded by a lag phase that was considerably longer in preadipocytes. This time span could not be explained by an induction of neprilysin nor by an increase in its surface localization. Following the lag phase, adipocytes showed a higher degradation activity than preadipocytes as mirrored by increased neprilysin levels and activity measured in their membrane fractions. Our findings demonstrate that human preadipocytes and adipocytes differentially express functional neprilysin and aminopeptidase activity involved in the regulation of angiotensin II concentrations in human adipose tissue.     

AT1 receptor blocker azilsartan medoxomil normalizes plasma miR-146a and miR-342-3p in a murine heart failure model

Our study measured circulating microRNA (miRNA) levels in the plasma of calsequestrin (CSQ)-tg mouse, a severe heart failure model, and evaluated whether treatment with angiotensin II type 1 receptor blocker, azilsartan medoxomil (AZL-M) influenced their levels using miRNA array analysis. MiR-146a, miR-149, miR-150, and miR-342-3p were reproducibly reduced in the plasma of CSQ-tg mice. Among them, miR-146a and miR-342-3p were significantly restored by AZL-M, which were associated with improvement of survival rate and reduction of congestion. These results suggest that miRNA, especially miR-146a and miR-342-3p, could be used as potential biomarkers for evaluating the efficacy of anti-heart failure drugs.     

Autoantibodies against serotoninergic 5-HT(4) receptor in patients with heart failure

Serotoninergic 5-HT(4) receptors have been detected in several tissues including the heart. An autoimmune mechanism may underline the pathogenesis of heart failure. The aim of this work was to look for autoantibodies to the 5-HT(4) receptor in patients with heart failure. We looked for the presence of autoantibodies against 5-HT(4) receptor as well as angiotensin II type (AT1), β(1)-adrenoceptor, and muscarinic M2 receptors in the sera of 176 patients with heart failure (female: n=96, male: n=80) and in 108 controls (female: n=69; male: n=39). The prevalence of 5-HT(4) receptor autoantibodies was 18.8% (n=33) in the group of patients with heart failure and 4.6% (n=5) in the control group (p<0.002). The prevalence of autoantibodies against AT1 was 1.7 (n=3), β(1)-adrenoreceptor 0.6 (n=1), and muscarinic-receptor M2 4.2 (n=5). Female patients with diabetes and heart failure had a positive trend (p=0.07) to the presence of 5-HT(4) receptor autoantibodies. In the group of female heart failure patients we found a significant correlation with the presence of coronary heart disease (p=0.05). The clinical relevance of 5-HT(4) receptor autoantibodies has to be further studied. The prevalence of 5-HT(4) receptor autoantibodies was highly significant in patients with chronic heart failure. It was also a significant correlation between these autoantibodies and the female subgroup with coronary heart disease. It is conceivable that the increased prevalence of autoantibodies against the 5-HT(4) receptor in patients with heart failure is more than just an epiphenomenon.     

Integrin-linked kinase is a central mediator in angiotensin II type 1- and chemokine receptor CXCR4 signaling in myocardial hypertrophy

Inflammation and pro-hypertrophic signaling are important for development and progression of myocardial hypertrophy (LVH) and chronic heart failure (CHF). Here we investigated the relevance of integrin-linked kinase (ILK) for chemokine receptor CXCR4- and angiotensin II type 1-triggered signaling and its regulation and role in cardiac remodeling.Using ELISA, real-time-PCR, and Western blotting, the present study demonstrates that SDF-1 and its receptor CXCR4 are up-regulated in plasma and left ventricles, respectively, in mouse models of cardiac hypertrophy (transaortic constriction, transgenic cardiac-specific overexpression of rac1) and in human CHF in association with increased cardiac ILK-expression. In isolated cardiomyocytes, ILK is activated by CXCR4-ligation and necessary for SDF-1-triggered activation of rac1, NAD(P)H oxidase, and release of reactive oxygen species. Importantly, the pro-hypertrophic peptide angiotensin II induces ILK-activation dependent on rac1 in cardiomyocytes, where ILK is necessary for angiotensin II-mediated stimulation of hypertrophy genes and protein synthesis.We conclude that in both SDF-1- and angiotensin II-triggered signaling, ILK is a central mediator of rac1-induced oxidative stress and myocardial hypertrophy.     

Angiotensin receptor blockers in heart failure after the ELITE II trial

Specific blockers of the angiotensin type1 receptor, angiotensin receptor blockers (ARBs), have been introduced as an alternative to angiotensin-converting enzyme inhibitors (ACEi) for the treatment of heart failure. In comparison with ACEi, ARBs are better tolerated and have similar effects on haemodynamics, neurohormones and exercise capacity. Early studies have suggested that ARBs might have a superior effect on mortality. However, the first outcome trial, ELITE II (Losartan Heart Failure Survival Study), did not show any significant difference between losartan and captopril in terms of mortality or morbidity. This commentary outlines the role of ARBs in the treatment of heart failure.