血管紧张素II及其受体在动脉粥样硬化中的作用

观察不同浓度血管紧张素Ⅱ及其受体在氧化低密度脂蛋白(OXLDL)内皮受体LOX1基因表达中的作用,且探讨其机制.应用反转录聚合酶链反应(RT-PCR)法.结果表明,血管紧张素Ⅱ能够上调LOXl的mRNA水平,并存在剂量依赖性应用Ⅰ型血管紧张素Ⅱ阻断剂Losartan能抑制血管紧张素Ⅱ对LOXl的上调作用.血管紧张素Ⅱ可显著上调LOXl的基因表达,此作用是通过激活血管紧张素Ⅰ型受体实现的.     

电性距离矢量(MEDV-B)用于58个血管紧张素转化酶(ACE)抑制剂二肽的结构表达

曾用β-受体阻滞剂治疗高血压,研究发现该类药物能减少肾素释放,目标始转肾素即血管紧张素系统试图获得更理想抗高血压药物.肾素是一种蛋白水解酶,可水解血管紧张素原,使Leu10-Val11肽键断裂为血管紧张素Ⅰ十肽,再在转化酶(ACE)作用下脱二肽转为血管紧张素Ⅱ八肽.     

小儿肾病综合症肾素-血管紧张素系统基因多态性研究

目的:探讨肾素-血管紧张素系统基因多态性与小儿肾脏疾病的关系及其意义。方法:用PCR方法检测4 0例肾病综合症患儿及5 0例正常对照组儿童的肾素-血管紧张素系统基因多态性。结果:①血管紧张素M2 35T基因多态性MM、MT、TT基因型肾病组分别为37 5 %、2 7 5 %、35 0 % ;对照组分别为6 6 0 %、18 0 %、16 0 % ,差异有显著性(P <0 0 5 )。②血管紧张素Ⅱ受体Ⅰ基因多态性AA、AC、CC基因型肾病组分别为4 5 0 %、2 7 5 %、2 7 5 % ,对照组分别为6 8 0 %、2 0 0 %、12 0 % ,差异无显著性(P >0 0 5 )。③血管紧张素转换酶基因多态性Ⅱ、DI、DD基因型肾病组分别为4 5 0 %、4 2 5 %、12 5 % ,对照组分别为4 6 0 %、4 4 0 %、10 0 % ,差异无显著性(P >0 0 5 )。其中难治性肾病组(2 0例)与非难治性肾病组(2 0例)比较、激素敏感组(2 9例)与激素耐药组(11例)比较,血管紧张素M2 35T基因多态性、血管紧张素Ⅱ受体Ⅰ基因多态性、血管紧张素转换酶基因多态性差异均无显著性(均P >0 0 5 )。结论:血管紧张素M2 35T基因TT型可能与小儿肾病综合症的发病密切相关;血管紧张素Ⅱ受体Ⅰ基因多态性、血管紧张素转换酶基因多态性与小儿肾病综合症的发病无关,未能证实肾素-血管紧张素系统基因多态性与疗效有关     

血管紧张素Ⅱ和内皮素在运动训练中对心血管系统作用的研究进展

血管紧张素Ⅱ(AngⅡ)和内皮素(ET)对人体具有广泛的生物学效应,在心血管系统的生理、病理过程中发挥作用。本文简要介绍血管紧张素Ⅱ和内皮素的生物学特性,并从不同强度运动对血管紧张素Ⅱ和内皮素的影响及血管紧张素Ⅱ和内皮素对运动时心血管系统的作用等方面进行综述。     

抗高血压药物临床治疗进展

高血压作为一种常见病、慢性病,在人群中具有较高的发病率,临床抗高血压药物的应用一直备受关注。本文以临床常用一线降压药物:利尿药、β受体阻滞剂、钙拮抗剂、血管紧张素转化酶抑制剂以及血管紧张素Ⅱ受体拮抗剂为讨论目标,分别对其作用机制、临床应用的研究进展进行综述。     

脑内血管紧张素及其在延髓对心血管活动的调节

血管紧张素（angiotensins,ANG）包括ANGⅠ、ANGⅡ、ANGⅢ、ANGⅣ,其受体亚型有AT1、AT2、AT4三种。一般认为,脑内血管紧张素的功能是由ANGⅡ与AT1受体结合完成的,但目前认为,脑内正常心血管功能是由ANG（1—7）与其特异性受体（AT5？）结合完成的;还有人指出,ANCⅢ与ANCⅡ在中枢效应中起着同等重要甚至比ANGⅡ更重要的作用。延髓腹外侧区（ventrolateralmedulla,VLM）是中枢重要的心血管活动的调控区域,在VLM通过氨基酸类神经递质影响心血管活动,并导致某些高血压的发生。     

CTGF mRNA在糖尿病大鼠心肌的表达及粉防己碱保护作用的研究

目的研究粉防己碱对糖尿病(DM)大鼠心肌的保护作用及相关机制.方法36只Wistar大鼠用链脲佐菌素(STZ)诱发糖尿病模型后,随机分为粉防己碱治疗组、苯那普利治疗组及糖尿病未治疗组,以10只正常大鼠作为对照.12周末检测血糖、血脂、心肌组织血管紧张素Ⅱ,应用RT-PCR检测心肌CTGR mRNA的表达水平.结果DM未治疗组心肌组织血管紧张素Ⅱ含量、CTGR mRNA的表达明显高于对照组和治疗组(P<0.01).结论持续高糖能导致心肌血管紧张素Ⅱ含量增高、CTGF mRNA表达增强,而粉防己碱能在一定程度上降低心肌血管紧张素Ⅱ含量,抑制CTGF mRNA表达,从而可能减轻糖尿病性心肌病的病理变化.     

血管紧张素转换酶抑制剂的作用与临床应用

血管紧和素转换酶抑制主要作用于紧素－血管紧张素系统，抑制血管紧张素Ⅱ的生成，延长缓激肽的扩血管作用，促使道列腺素释放，是近年来进展最 血管扩张剂。已广泛应用于心血管疾病的治疗。     

盐酸贝那普利致体位性咳嗽的探讨

盐酸贝那普利是一种降压药,本品在肝脏内水解为贝那普利拉,成为一种竞争性的血管紧张素转换酶抑制剂,使血管紧张素Ⅰ不能转换为血管紧张素Ⅱ,结果血管阻力降低,醛固酮分泌减少,血浆肾素活性增高。     

Ⅰ型、Ⅱ型和Ⅲ型TGF-β受体在胃癌及癌前病变中的表达

应用免疫组化SABC方法检测正常胃粘膜(20例)、肠化生(18例)、不典型增生(20例)及胃癌(30例)中Ⅰ型、Ⅱ型和Ⅲ型TGF β受体的表达,以表达的阳性率进行统计学分析。结果表明,正常胃粘膜、肠化生、不典型增生及胃癌中,Ⅰ型TGF β受体表达递减(P<0.05);Ⅱ型TGF β受体表达递减(P<0.05),与胃癌的浸润深度及淋巴结转移呈负相关(P<0.05);Ⅲ型TGF β受体表达极低,并且在各组间表达无显著差异(P>0.05)。说明:Ⅰ型、Ⅱ型TGF β受体可能在胃癌的发生、发展中起着关键性的作用。     

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.     

Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor

Angiotensin II elicits different responses which affect cardiovascular, neuronal and electrolyte transport regulation. To understand the mechanisms responsible for its various actions, the receptor for angiotensin II has long been sought, but numerous attempts to purify the receptor have been unsuccessful owing to its instability and low concentration. We report here the expression cloning of a complementary DNA encoding a bovine angiotensin II receptor to overcome these difficulties. The receptor cDNA encodes a protein of 359 amino-acid residues with a transmembrane topology similar to that of other G protein-coupled receptors. COS-7 cells transfected with the cDNA expressed specific and high-affinity binding sites for angiotensin II, angiotensin II antagonist and a non-peptide specific antagonist for type-1 receptor. Dithiothreitol inhibited ligand binding. The concentration of intracellular Ca2+ and of inositol-1,4,5-trisphosphate increased in the transfected COS-7 cells in response to angiotensin II or angiotensin III, indicating that this receptor is the type-1 receptor for angiotensin II. Northern blot analysis revealed that the messenger RNA for this receptor is expressed in bovine adrenal medulla, cortex and kidney.     

Losartan reduced connexin43 expression in left ventricular myocardium of spontaneously hypertensive rats

Objective： To assess the effect of angiotensin II type 1 （AT1） receptor antagonist losartan on myocardium connexin43 （Cx43） gap junction （GJ） expression in spontaneously hypertensive rats （SHRs） and investigate possible mechanisms. Methods： Sixteen 9-week-old male SHRs and 8 age-matched male Wistar-Kyoto （WKY） rats were included in this study. SHRs were randomly divided into two groups to receive losartan at 30 mg/（kg·d） by oral gavage once daily for 8 weeks （SHR-L） or vehicle （0.9% saline） to act as controls （SHR-V）; WKY rats receiving vehicle for 8 weeks served as normotensive controls. At the end of the experiment, rats were sacrificed and the hearts were removed. Expressions of Cx43 and nuclear factor-kappaB p65 （NF-κB p65） proteins in all three groups were observed and further investigations on the effect of angiotensin II type 1 receptor antagonist losartan （30 mg/（kg·d）, 8 weeks） on Cx43 expression were conducted with Western blot and immunohistochemistry. NF-κB p65 protein in nuclear extracts was determined by Western blot. Results： Left ventricular （LV） hypertrophy was prominent in SHRs, Cx43 and NF-κB p65 protein expressions were obviously upregulated and Cx43 distribution was dispersed over the cell surface. Treatment with losarton reduced the over-expressions of Cx43 and NF-κB p65 in LV myocardium. The distribution of Cx43 gap junction also became much regular and confined to intercalated disk after losartan treatment. Conclusion： Cx43 level was upregulated in LV myocardium of SHR during early stage of hypertrophy. Angiotensin II type 1 receptor antagonist losartan prevented Cx43 gap junction remodeling in hypertrophied left ventricles, possibly through the NF-κB pathway.     

AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration

The vasopressor angiotensin II regulates vascular contractility and blood pressure through binding to type 1 angiotensin II receptors (AT1; refs 1, 2). Bradykinin, a vasodepressor, is a functional antagonist of angiotensin II (ref. 3). The two hormone systems are interconnected by the angiotensin-converting enzyme, which releases angiotensin II from its precursor and inactivates the vasodepressor bradykinin. Here we show that the AT1 receptor and the bradykinin (B2) receptor also communicate directly with each other. They form stable heterodimers, causing increased activation of G alpha(q) and G alpha(i) proteins, the two major signalling proteins triggered by AT1. Furthermore, the endocytotic pathway of both receptors changed with heterodimerization. This is the first example of signal enhancement triggered by heterodimerization of two different vasoactive hormone receptors.     

Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor

Angiotensin II is an important effector molecule controlling blood pressure and volume in the cardiovascular system. Its importance is manifested by the efficacy of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Angiotensin II interacts with two pharmacologically distinct subtypes of cell-surface receptors, AT1 and AT2. AT1 receptors seem to mediate the major cardiovascular effects of angiotensin II. Here we report the isolation by expression cloning of a complementary DNA encoding a unique protein with the pharmacological specificity of a vascular AT1 receptor. Hydropathic modelling of the deduced protein suggests that it shares the seven-transmembrane-region motif with the G protein-coupled receptor superfamily. Knowledge of the AT1 receptor primary sequence should now permit structural analysis, definition of the angiotensin II receptor gene family and delineation of the contribution of AT receptors to the genetic component of hypertension.     

Regulation by angiotensin II of its receptors in resistance blood vessels

The sensitivity of blood vessels to the vasoconstrictor effects of the hormone angiotensin II appears to be modulated by the activity of the renin-angiotensin system. Elevation of circulating angiotensin II levels by sodium depletion or renal artery stenosis is associated with a diminished pressor response to infused angiotensin II (refs 1-3). Conversely, the vasocontrictor response to the hormone is enhanced when endogenous angiotensin II levels are reduced by sodium loading or nephrectomy. The mechanisms of these varying effects are not known, but physiological and pharmacological experiments suggest involvement of the vascular smooth receptor for angiotensin II (refs 5-8). Modification of the interaction between angiotensin II and its vascular receptor, resulting in altered responsiveness to the hormone, could occur either via 'prior occupancy' of receptors by elevated levels of endogenous angiotensin II resulting in fewer free receptors available to respond to circulating angiotensin II (ref. 5), or, elevated levels of angiotensin II could result in a decrease in receptor affinity for the hormone or a decrease in total receptor number in the vascular smooth muscle cell. We now report the first direct evidence, by radioligand binding assay, that angiotensin II regulates the number of its own receptors in resistance vasculature.     

Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene.

Glucocorticoids, in conjunction with their cognate receptors, exert negative-feedback effects on the hypothalamus-pituitary-adrenal axis, suppressing adrenal steroid secretions. Two types of corticosteroid receptor, distinguishable by their ability to bind corticosterone, have been identified as classical mineralocorticoid (type I) and glucocorticoid (type II) receptors by cloning their complementary DNAs. The type I receptor controls the basal circadian rhythm of corticosteroid secretion. Both receptor types are involved in negative feedback, but the type II receptor may be more important for terminating the stress response as it is the only one to be increased in animals rendered more sensitive to corticosteroid negative-feedback effects. Here we create a transgenic mouse with impaired corticosteroid-receptor function by partially knocking out gene expression with type II glucocorticoid receptor antisense RNA. We use this animal to study the glucocorticoid feedback effect on the hypothalamus-pituitary-adrenal axis.     

Regulation of angiotensinⅡon Gαq/11 protein of vascular smooth muscle cell and its underlying mechanism

To study the regulation of angiotensin Ⅱ(Ang Ⅱ) on Gαq/11 protein of vascular smooth muscle cell (VSMC) and its underlying mechanism, the protein synthesis was detected by [³H]-leucine incorporation. Gαq/11 expression was measured by Western blot in cultured VSMC of rat aorta. The results showed that the level of Gαq/11 was downregulated after stimulated by AngⅡ for 1—6 h, while it was upregulated significantly by 12—24 h stimulation (P < 0.01) in VSMC. The [³H]-leucine incorporation of VSMC was increased after 24 h Ang Ⅱ stimulation. The biphase regulation of Ang Ⅱ on Gαq/11 protein was blocked by the Ang Ⅱ type Ⅰ receptor (AT1) specific antagnist losartan or PLC inhibitor U73122, while PD98059 did not have this effect. These data indicated that Ang Ⅱ contributed to VSMC hypertrophy by regulating the level of Gαq/11, and this effect was mediated mainly through AT1 receptor-PLC signal transduction pathway.     

Coiled-coil fibrous domains mediate ligand binding by macrophage scavenger receptor type II

The macrophage scavenger receptor, which has been implicated in the pathogenesis of atherosclerosis, has an unusually broad binding specificity. Ligands include modified low-density lipoprotein and some polyanions (for example, poly(I) but not poly(C]. The scavenger receptor type I (ref. 3) has three principal extracellular domains that could participate in ligand binding: two fibrous coiled-coil domains (alpha-helical coiled-coil domain IV and collagen-like domain V), and the 110-amino-acid cysteine-rich C-terminal domain VI. We have cloned complementary DNAs encoding a second scavenger receptor which we have termed type II. This receptor is identical to the type I receptor, except that the cysteine-rich domain is replaced by a six-residue C terminus. Despite this truncation, the type II receptor mediates endocytosis of chemically modified low-density lipoprotein with high affinity and specificity, similar to that of the type I receptor. Therefore one or both of the extracellular fibrous domains are responsible for the unusual ligand-binding specificity of the receptor.