ACE2-Ang-（1—7）-Mas轴：心血管疾病治疗的新靶点

肾素一血管紧张素系统(RAS)在哺乳动物心血管活动的调节中发挥了重要的作用.随着血管紧张素转化酶(ACE)2和血管紧张素1-7[Ang-(1-7)]特异性受体Mas的发现,形成了RAS中一个对心血管有益的新分支:ACE2-Ang-(1-7)-Mas轴.其中ACE2可以水解血管紧张素Ⅰ(Ang Ⅰ)、血管紧张素Ⅱ(AngⅡ)生成Ang-(1-7).Ang-(1-7)则通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖.这一新分支的发现为心血管疾病的治疗提供了新靶点.     

血管紧张素Ⅱ1型和2型受体

肾素 血管紧张素系统 (RAS)在维持人体心脏血管和神经内分泌体液平衡中起十分重要的作用 ,血管紧张素Ⅱ (AngⅡ )是该系统的主要活性肽 ,作用于血管紧张素Ⅱ受体 ,产生相应的生物学效应。过去认为AngⅡ在体内是由血管紧张素I(AngⅠ )在血管紧张素转化酶 (ACE)作用下生成的含有 8个氨基酸的多肽 ,现在认为AngⅡ产生除ACE经典途径外还有组织蛋白酶G、胃促胰酶、激肽释放酶、胰蛋白酶等非经典途径 ,血管紧张素转化酶抑制剂 (ACEI)可抑制ACE途径 ,但不抑制其它途径产生的AngⅡ ,所以不能完全阻断AngⅡ的产生。AngⅡ受体拮抗剂是在受…     

血管紧张素-(1-7)在心血管系统中的作用

血管紧张素-(1-7)是肾素-血管紧张素系统中具有重要生物学作用的终末活性产物,可通过直接作用于心血管中枢调节心血管活动以及与心脏和血管上特异性受体结合而发挥改善心功能、降低血压、抑制心脏和血管重构作用.现就血管紧张素-(1-7)对心血管系统中的作用综述如下.     

血管紧张素转换酶2研究新进展

血管紧张素转换酶(ACE)是一种锌指金属蛋白酶,对肾素-血管紧张素系统(RAS)有关键调控作用.ACE 2主要分布在心脏、肾脏和睾丸,能水解血管紧张素(Ang)Ⅰ,产生Ang 1-9,还能水解RAS中的主要物质AngⅡ,产生具有血管扩张作用的Ang 1-7.研究表明ACE 2可能在RAS中扮演与ACE相反的角色,达到血管收缩和舒张之间的平衡,与高血压、心力衰竭及糖尿病肾病等关系密切.     

血管紧张素转换酶2基因多态性与肾脏损害

肾素血管紧张素系统（RAS）是体内调节神经体液和心血管功能的主要系统。新发现的多肽酶血管紧张素转换酶2（ACE2）通过产生血管紧张素（Ang）1-7和水解部分AngⅡ,拮抗由ACE水解产物AngⅡ介导的缩血管作用，并抑制血管平滑肌细胞增殖。研究表明糖尿病大鼠肾脏ACE2表达下降，糖尿病、高血压和代谢综合征均可损害肾脏，本研究旨在探讨这三种疾病患者ACE2基因A/C多态分布情况及其与肾脏损害的关系。     

血管紧张素-(1-7)的心血管调节作用

血管紧张素-(1-7)是肾素血管紧张素系统家族中的新成员,近来研究提示其有抗高血压、抑制血管平滑肌增殖和心肌细胞肥大、影响心脏神经电生理、抗血栓形成、调节水、电解质代谢平衡等作用,是血管紧张素Ⅱ(AngⅡ)的内源性拮抗剂。     

血管紧张素1-7：肾素-血管紧张素系统新调节因子

血管紧张素（Ang）1-7是肾素-血管紧张素系统的新调节因子，它能够拮抗AngⅡ的扩血管和促增殖等效应，并对肾脏发挥复杂的调节作用。通过药物作用干预血管紧张素酶2-Ang-（1-7）-Mas轴的功能，将会为心血管疾病、肾脏、肝脏疾病和糖尿病的治疗提供新的可能。     

ACE2-Ang(1-7)-Mas轴与心房颤动的关系

在肾素-血管紧张素系统(RAS)中,血管紧张素转化酶2(ACE2)与血管紧张素(AngⅡ)之间的代谢关系在ACE2-Ang(1-7)-Mas轴保护心房颤动(房颤)的心肌细胞作用中发挥着重要作用.作为ACE的唯一同系物,ACE2可以水解AngⅡ为七肽Ang(1-7),而Ang(1-7)可以特异性激活Mas受体,发挥抗纤维...     

ACE2-Ang-（1—7）-Mas轴：心血管疾病治疗的新靶点

肾素-血管紧张素系统（RAS）在哺乳动物心血管活动的调节中发挥了重要的作用。随着血管紧张素转化酶（ACE）2和血管紧张素1—7[Ang-（1-7）]特异性受体Mas的发现,形成了RAS中一个对心血管有益的新分支：ACE2-Ang-（1-7）-Mas轴。其中ACE2可以水解血管紧张素Ⅰ（AngⅠ）、血管紧张素Ⅱ（AngⅡ）生成Ang-（1-7）。Ang（1-7）则通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖。这一新分支的发现为心血管疾病的治疗提供了新靶点。     

血管紧张素转化酶2和其主要产物Ang(1-7)生物作用

肾素-血管紧张素系统（RAS）是一个重要的血压和水电解质调节系统。经典的RAS是指由肝脏分泌的血管紧张素原释放入血液循环，在肾近球细胞产生的肾素作用下转化为10肽的血管紧张素Ⅰ（AngⅠ），再经肺循环的血管紧张素转化酶（ACE）的作用转化为8肽的血管紧张素Ⅱ（AngⅡ）。近年来，研究发现除上述经典（循环RAS）外，局部组织如心脏、血管壁、肾脏、脑等组织还具有独立的RAS，主要凋节局部组织的生长和分化，循环和局部的RAS在心血管疾病中起非常重要的作用。     

血管紧张素转换酶2与糖尿病

肾素-血管紧张素系统（RAS）的过度激活在糖尿病及其慢性并发症的发生发展中发挥重要作用。血管紧张素转换酶（ACE）2作为RAS的新成员,可高效水解血管紧张素（Ang）Ⅱ生成Ang（1-7）,并竞争性作用于ACE的底物AngⅠ,与ACE共同调节RAS稳态。ACE2可改善胰岛血供、胰岛素分泌、减少胰岛纤维化及胰岛素抵抗,并延缓糖尿病慢性并发症的发生发展。深入研究ACE2,对防治糖尿病及其慢性并发症具有重要意义。     

血管紧张素转化酶2与糖尿病慢性并发症

肾素-血管紧张素系统（RAS）的过度激活在糖尿病及其慢性并发症的发生发展中发挥重要作用。血管紧张素转化酶（ACE）2是近年新发现的ACE的同系物，ACE2通过ACE2-Ang（1—7）-Mas受体轴拮抗经典ACE—AngⅡ—AngⅡ1型受体（ATI）轴发挥扩张血管、抗增殖、抗纤维化等作用，ACE2可改善胰岛血供，增加胰岛素分泌、延缓糖尿病并发症的发生，以ACE2为靶点的研究对于防治糖尿病及其并发症具有重要意义。     

Central angiotensin I increases swallowing activity and oxytocin release in the near-term ovine fetus

The brain renin-angiotensin system (RAS) plays an important role in hydromineral and neuroendocrine balance. Although previous studies showed that exogenous angiotensin (Ang) II increased dipsogenic and vasopressin responses in near-term fetuses, little is known about the functional development of fetal endogenous brain RAS in the regulation of body fluid homeostasis. To determine the functional development of the central angiotensin-converting enzyme (ACE) in utero, we investigated the electrocortical (ECoG) activity, swallowing activity, oxytocin (OT) release, and c-fos expression in response to intracerebroventricular Ang I administration in the near-term fetal lamb. Ang I did not change fetal low-voltage (LV) and high-voltage (HV) ECoG temporal distributions, but increased fetal swallowing activity during LV ECoG (1.0±0.1 to 3.5±0.4 swallows/min). Additionally, Ang I evoked an increase in c-fos-immunoreactivity in putative dipsogenic centers, including the supraoptic and paraventricular nuclei of the hypothalamus, accompanied by an increase in fetal plasma OT levels. The expression of c-fos was demonstrated in OT neurons in the hypothalamus. The Ang I-mediated increase in fetal swallowing and plasma OT was inhibited by captopril. These results demonstrate the functional development of the fetal brain ACE system in the last trimester of gestation, which plays an important role in the RAS-mediated dipsogenic response and OT release in the regulation of body fluid homeostasis.     

Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension

There is a growing body of evidence that the advanced glycation end product (AGE)-their receptor (RAGE) system plays a central role in the pathogenesis of diabetic vascular complication. The renin-angiotensin system (RAS) contributes to the development and progression of diabetic angiopathy as well. However, the cross-talk between the AGE-RAGE system and the RAS is not fully understood. In this study, we examined the role of angiotensin II (Ang II) type 1 receptor system for RAGE expression in cultured endothelial cells (ECs) and in patients with essential hypertension. Ang II up-regulated RAGE mRNA levels of microvascular ECs and subsequently increased the soluble form of RAGE (sRAGE) expression in the medium of ECs, both of which were completely blocked by telmisartan, a commercially available Ang II type 1 receptor antagonist. Furthermore, telmisartan was found to decrease serum levels of sRAGE in patients with essential hypertension. These results demonstrate that sRAGE is released from the cell surface of Ang-II-exposed ECs. Our present study indicates that a cross-talk exists between the AGE-RAGE system and the RAS and suggests that serum levels of sRAGE may reflect endothelial RAGE expression.     

Angiotensin AT1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

Aims/hypothesis The renin angiotensin system is emerging as a potential therapeutic target for diabetic retinopathy. This study examines the effects of angiotensin-converting-enzyme inhibition by captopril and angiotensin AT₁ receptor antagonism using candesartan-cilexetil on retinal blood flow and acetylcholine-stimulated vasodilatation in normotensive diabetic rats.Methods Non-diabetic or streptozotocin-induced diabetic rats were treated for 2 weeks with captopril (100 mg/kg/day) or candesartan cilexetil (2 mg/kg/day). Retinal haemodynamics were measured using video fluorescein angiography. Effects of exogenous acetylcholine on retinal haemodynamics were examined following intravitreal injection. Total retinal diacylglycerol was labelled using diacylglycerol kinase, separated by thin-layer chromatography, and quantified using autoradiography.Results Diabetic rats had prolonged retinal mean circulation time and decreased retinal blood flow compared with non-diabetic rats. Treatment of diabetic rats with either captopril or candesartan blocked the development of these blood flow abnormalities. Intraviteral injection of acetylcholine (10^–5 mol/l) in non-diabetic rats increased retinal blood flow by 53.9±22.0% relative to baseline whereas this response to acetylcholine was blunted in diabetic rats (4.4±19.6%, p<0.001). Candesartan treatment of diabetic rats restored the acetylcholine-stimulated retinal blood flow response to 60.0±18.7% compared with a 56.2+20.1% response in candesartan-treated non-diabetic rats. Total retinal diacylglycerol levels were increased in diabetic rats (3.75±0.98 nmol/mg, p<0.05) compared with non-diabetic rats (2.13±0.25 nmol/mg) and candesartan-treatment of diabetic rats normalized diacylglycerol levels (2.10±0.25 nmol/mg, p<0.05).Conclusion/interpretation This report provides evidence that angiotensin-converting enzyme inhibition and AT₁ receptor antagonism ameliorates retinal haemodynamic dysfunctions in normotensive diabetic rats.Abbreviations ACh acetylcholine - AT appearance time - DAG diacylglycerol - DM diabetic - MCT mean circulation time - NDM non-diabetic - RAS renin angiotensin system - RBF retinal blood flow - STZ streptozotocin     

Dysregulation of the Renin-Angiotensin System and the Vasopressinergic System Interactions in Cardiovascular Disorders

Purpose of Review

In many instances, the renin-angiotensin system (RAS) and the vasopressinergic system (VPS) are jointly activated by the same stimuli and engaged in the regulation of the same processes.

Recent Findings

Angiotensin II (Ang II) and arginine vasopressin (AVP), which are the main active compounds of the RAS and the VPS, interact at several levels. Firstly, Ang II, acting on AT1 receptors (AT1R), plays a significant role in the release of AVP from vasopressinergic neurons and AVP, stimulating V1a receptors (V1aR), regulates the release of renin in the kidney. Secondly, Ang II and AVP, acting on AT1R and V1aR, respectively, exert vasoconstriction, increase cardiac contractility, stimulate the sympathoadrenal system, and elevate blood pressure. At the same time, they act antagonistically in the regulation of blood pressure by baroreflex. Thirdly, the cooperative action of Ang II acting on AT1R and AVP stimulating both V1aR and V2 receptors in the kidney is necessary for the appropriate regulation of renal blood flow and the efficient resorption of sodium and water. Furthermore, both peptides enhance the release of aldosterone and potentiate its action in the renal tubules.

Summary

In this review, we (1) point attention to the role of the cooperative action of Ang II and AVP for the regulation of blood pressure and the water-electrolyte balance under physiological conditions, (2) present the subcellular mechanisms underlying interactions of these two peptides, and (3) provide evidence that dysregulation of the cooperative action of Ang II and AVP significantly contributes to the development of disturbances in the regulation of blood pressure and the water-electrolyte balance in cardiovascular diseases.

     

Effect of renin–angiotensin system on senescence

The renin–angiotensin system (RAS) plays crucial roles in the control of blood pressure and sodium homeostasis. Moreover, RAS also acts as a key player in cell and organ senescence, mainly by activation of the classical axis of angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 receptor via overproduction of reactive oxygen species. Overactivation of the classical RAS axis induces organ dysfunction in the vasculature, brain, kidney and skeletal muscle, resulting in atherosclerosis, stroke, chronic kidney disease and sarcopenia. Moreover, RAS has been shown to regulate lifespan, using gene‐modification models. Recently, mice lacking the Ang II type 1 receptor were shown to exhibit an increase in lifespan compared with control mice. Here, the effect of RAS on age‐related tissue dysfunction in several organs is reviewed, including not only the classical axis but also protective functions of RAS such as the ACE2/Ang (1–7)/Mas axis. Geriatr Gerontol Int 2020; ??: ??–?? .