Relationship between angiotensin-(1-7) and angiotensin Ⅱ correlates with hemodynamic changes in human liver cirrhosis

AIM： To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system （RAS） components and hemodynamic changes. METHODS： Patients were allocated into 4 groups： mild-to-moderate liver disease （MLD）, advanced liver disease （ALD）, patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity （PRA）, angiotensin （Ang） Ⅰ, Ang Ⅱ, and Ang-（1-7） levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS： PRA and angiotensins were elevated in ALD when compared to MLD and controls （P 〈 0.05）. In contrast, Ang Ⅱ was significantly reduced in MLD. Ang-（1-7）/Ang Ⅱ ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang Ⅱ levels were lower and Ang-（1-7）/Ang Ⅱ ratios were higher in the splanchnic circulation than in the peripheral circulation （0.52 ± 0.08 vs 0.38 ±0.04, P 〈 0.02）, whereas the peripheral circulating Ang Ⅱ/Ang Ⅰ ratio was elevated in comparison to splanchnic levels （0.18 ±0.02 vs 0.13 ±0.02, P 〈 0.04）. Ang-（1-7）/ Ang Ⅱ ratios positively correlated with cardiac output （r = 0.66） and negatively correlated with systemic vascular resistance （r = -0.70）. CONCLUSION： Our findings suggest that the relationship between Ang-（1-7） and Ang Ⅱ may play a role in the hemodynamic changes of human cirrhosis.

Effects on Cell Viability and on Apoptosis in Tumoral(MCF-7)and in Normal(MCF10A)Epithelial Breast Cells after Human Chorionic Gonadotropin and Derivated-Angiotensin Peptides Treatments

Angiotensin-(1 - 7) [Ang-(1 - 7)] is an endogenous heptapeptide hormone of the renin-angiotensin system that has antiproliferative properties. The aim of this work was to evaluate the anti-proliferative and pro-apoptotic properties of Ang-(1 - 7) and of Ang-(1 - 7)-substituents 9-fluorenylmethyloxycarbonyl (Fmoc) e Ang II-derivatives containing the TOAC (2,2,6,6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid) in normal (MCF10A) and in tumoral (MCF7) epithelial mammary cell lines. Both cell lines received an hCG and angiotensin peptides 24-hour treatment, in combination or alone followed by cell viability, apoptosis and cell cycle assays performed by flow cytometer (GUAVA). After hCG, Ang-(1 - 7), hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments, MCF7 displayed cell viability decrease and mid-apoptosis increase. We also observed cell viability decrease in MCF10A after Ang-(1 - 7), Ang-(1 - 7) Fmoc and hCG + AngII Toac treatments. These cells had an increase in late apoptosis and necrosis after AngII Toac, hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments. Regarding the cell cycle analysis, we did not observed any changes in cell cycle phases. In summary, cell viability was decreased and apoptosis (initial, mid and late) was increased after hCG and/or Ang-(1 - 7) peptides treatments. These results point out hCG and Ang-(1 - 7) as effective compounds to inhibit cell proliferation, since they decrease cell viability and increase apoptosis in both normal and in tumoral breast cells, being the effect more pronounced in the tumoral cell line. Our results support the idea of investigating more closely the putative use of these compounds as novel therapeutic agents for breast cancer.

A Study of the Correlation between Angiotensin (1-7) and the Histopathological Changes in the Penises of Experimentally Diabetic Rats

Background: Diabetes mellitus is an important risk factor for erectile dysfunction. Renin-angiotensin system with its branches Angiotensin II and Angiotensin 1-7 [Ang-(1-7)] are altered in diabetes and could affect erection. So, in this study we determine the level of Ang-(1-7), nitrite (the major nitric oxide metabolite) and histopathological changes in penile tissues of type I diabetic rats. A total of 60 male albino rats were divided into two groups: group I (control) and group II (diabetic) for either 4 weeks in group IIa, or 8 weeks in group IIb. Diabetes was induced by intraperitoneal injection of streptozotocin (60 mg/kg). Penile levels of Ang-(1-7), nitrite and histopathological examination were assessed at 4 and 8 weeks after diabetes induction. Results: Ang-(1-7) and nitrite were decreased in diabetic rats at 4 weeks and continued to be lower at 8 weeks for Ang-(1-7) only. Loss of corpus cavernosum smooth muscle was present in 25% and 85% of rats at 4 and 8 weeks of diabetes respectively (P Conclusion: Diabetes induced progressive decrease in the release of Ang-(1-7) and nitric oxide from the corpora cavernosa in a time-dependent manner with concomitant fibro-muscular changes that end by corporal fibrosis affecting subsequently erectile functions.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

Advances in angiotensin-(1-7) and atrial fibrillation

Atrial fibrillation (AF) is one of the most common arrhythmias in clinic. Atrial fibrillation and its complications are one of the important causes of death. Despite the development of new therapies, including catheter ablation, the treatment of atrial fibrillation remains an important and arduous task. Current studies on the mechanism of atrial fibrillation show that the occurrence and development of atrial fibrillation mainly involves the electrophysiological mechanism of the heart and the pathophysiological mechanism of the heart. Atrial remodeling plays an important role in the process of atrial fibrillation. Atrial remodeling includes electrical remodeling of atrial structure. The early stage of atrial remodeling is characterized by electrophysiological and ion channel changes, while the late stage is characterized by amyloidosis and fibrosis of extracellular matrix and atrial muscle. Angiotensin-converting enzyme 2 and angiotensin-(1-7) are important components of renin-angiotensin-aldosterone system. Recent studies have shown that angiotensin - (1-7) plays an important protective role in the occurrence and development of atrial fibrillation. In this paper, the relationship between angiotensin - (1-7) and atrial remodeling during atrial fibrillation and its research progress are reviewed.

Effect of angiotensin 1-7 on endothelial cell injury caused by oxidative stress

Objective:To study the effects of angiotensin 1-7 (Ang1-7) on endothelial cell injury caused by oxidative stress.Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and divided into blank control group, hydrogen peroxide and different Ang1-7 dose groups (1, 2 and 4 μmol/L Ang1-7 groups). The cell proliferation activity, the contents of antioxidant enzymes in cell culture medium, and the contents of endoplasmic reticulum stress molecules in cells were determined.Results: After 6, 12, 18 and 24 h of treatment, CCK-8 proliferation activity values of hydrogen peroxide group were significantly lower than those of blank control group, CCK-8 proliferation activity values of 1, 2 and 4 μmol/L Ang1-7 groups were significantly higher than those of hydrogen peroxide group, and the larger the Ang1-7 dose, the higher the CCK-8 proliferation activity values;after 24 h of treatment, SOD, GSH-Px, HO-1 and CAT contents in cell culture medium of hydrogen peroxide group were significantly lower than those of control group, and GRP78, XBP1 and CHOP contents in cells were significantly higher than those of control group;SOD, GSH-Px, HO-1 and CAT contents in cell culture medium of 1, 2 and 4 μmol/L Ang1-7 groups were significantly higher than those of hydrogen peroxide group, GRP78, XBP1 and CHOP contents in cells were significantly lower than those of hydrogen peroxide group, and the larger the Ang1-7 dose, the more significant the changes of above molecules in cell culture medium and cells.Conclusion: Angiotensin 1-7 has protective effect on the endothelial cell injury caused by oxidative stress.

Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system

The present letter to the editor is related to the study titled‘Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells’.Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

ACE2/Ang(1-7)对小鼠脂肪组织脂肪合成的影响

目的探讨血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)-血管紧张素(1-7)[angiotensin(1-7),Ang(1-7)]对小鼠脂肪组织脂肪合成的影响。方法选取雄性ACE2基因敲除模型小鼠及野生C57BL/6(wild-type,WT)对照小鼠,测体质量,计算体脂率,测定血清三酰甘油(triglycerides,TG)及总胆固醇(total cholesterol,TC)浓度,HE染色观察附睾脂肪细胞形态学变化,蛋白印记(Western blotting)法检测附睾脂肪组织脂肪合成因子乙酰辅酶A羧化酶α(acetyl-Co A carboxylaseɑ,ACCα)、脂肪酸合成酶(fatty acid synthetase,FAS)及脂肪型脂肪酸结合蛋白(adipocyte fatty acid binding protein,a P2)的表达。将雄性db/db小鼠采用数字表法随机分为3组,分别给予0.9%(质量分数)氯化钠注射液,Ang(1-7),Ang(1-7)+A779[Ang(1-7)的拮抗剂]皮下泵入干预4周。测体质量,Western blotting法检测小鼠附睾脂肪组织脂肪合成因子蛋白的表达。结果 ACE2基因敲除小鼠体脂率及血TG浓度明显高于野生对照小鼠。Western blotting法检测结果表明ACE2基因敲除小鼠附睾脂肪组织脂肪合成因子ACCα及FAS蛋白表达明显高于野生对照组。应用Ang(1-7)干预2型糖尿病db/db小鼠显著抑制其附睾脂肪组织脂肪合成因子ACCα及FAS蛋白表达,而应用Ang(1-7)拮抗剂A779拮抗了这一作用。结论 ACE2/Ang(1-7)抑制白色脂肪合成,其机制可能是通过抑制脂肪合成相关因子的表达发挥作用。

血管紧张素1-7减弱醋酸去氧皮质酮盐型高血压大鼠的左心室重构

目的观察血管紧张素1-7(angiotensin 1-7,Ang 1-7)对醋酸去氧皮质酮(deoxycorticosterone acetate,DOCA)盐敏感性高血压大鼠的左心室肥厚及心肌纤维化的影响及其可能机制。方法♂SD大鼠,行左肾切除术后皮下注射DOCA,并饮用1%氯化钠溶液4周,建立DOCA-盐型高血压模型。在模型建立的同时,使用植入大鼠背部皮下的Alzet微渗透泵慢性灌流Ang1-7 4周,剂量为200 ng·kg-1·min-1。对照组给予生理盐水。测量大鼠的动脉血压和左心室功能,并在HE染色标本测量心肌细胞面积,在天狼星红染色标本测量心肌纤维化面积。Real-time PCR法检测大鼠心肌组织的心房利钠因子(ANF)和β-肌球蛋白重链(β-MHC)mRNA的表达,蛋白免疫印迹法观察心肌组织TGF-β1蛋白的表达变化。结果 DOCA盐型大鼠在模型建立的第1周开始,出现动脉血压的明显增加,在第4周末达峰值;同时其左室收缩末期压(LVESP)、左室舒张末期压(LVEDP)和心室收缩时室内压最大上升速率(+dp/dt)也发生明显变化。慢性灌流Ang 1-7后DOCA盐型大鼠的4周末的动脉血压、LVESP和LVEDP均明显降低,而+dp/dt明显增加(P<0.05,n=7)。Ang 1-7灌流可以明显降低DOCA盐型大鼠的心脏指数和心肌细胞面积,以及上调的ANF和β-MHC mRNA表达(P<0.05,n=7)。同时,Ang 1-7也可明显降低DOCA盐型大鼠的血管周围纤维化和间质纤维化面积,并明显抑制DOCA盐型大鼠增加的TGF-β1表达(P<0.05,n=7)。结论 Ang 1-7可以通过降低DOCA盐型高血压大鼠的动脉血压和改善左心室肥厚和心肌纤维化,而发挥心脏保护效应。

Losartan Protects Podocytes against High Glucose-induced Injury by Inhibiting B7-1 Expression

The role of B7-1 in podocyte injury has received increasing attention.The aim of this study was to investigate whether losartan protects podocytes of patients with diabetic kidney disease(DKD)by regulating B7-1 and the underlying mechanisms.Rats with streptozotocin-induced DKD were treated with losartan for 8 weeks.Biochemical changes in blood and urine were analyzed.Kidneys were isolated for electron microscopy,immunofluorescence,real-time quantitative PCR(RT-PCR),and Western blot analysis.Immortalized mouse podocyte cells were cultured in normal or high glucose medium in the presence or absence of losartan for 48 h,and then the cells were collected for immunofluorescence,PCR,Western blotting and monolayer permeability detection.The phosphatidylinositol 3-kinase(PI3K)110a subunit and angiotensin II type 1 receptor(AT1R)plasmids were transfected into podocytes,respectively,and then Western blotting was performed to assess the expression of B7-1 protein.The results showed that losartan ameliorated podocyte structure and function in the rat model of DKD,and reduced the expression of B7-1 protein.Overexpression of PI3K 110a subunit in podocytes attenuated the inhibitory effect of losartan on B7-1 expression in high glucose-stimulated podocytes.The expression of B7-1 was significantly increased by overexpression of ATI R and significantly reduced by blocking PI3K 110a subunit.We conclude that losartan protects podocytes against high glucose-induced injury by inhibiting AT1R-mediated B7-1 expression.This effect is dependent on the AT1R-PI3K 110a subunit pathway.

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.

Renin-angiotensin system blockade: Effect on renal mRNA expression in 5/6 nephrectomized rats

The aim of this study was to determinate the gene expression levels of angiotensinogen, angiotensin converting enzyme, renin, (pro)renin receptor, and the final rennin-angiotensin system (RAS) products Angiotensin (Ang) II and Ang 1-7 inthe remnant kidney of 5/6 nephrectomized rats and its response to RAS pharmacological blockade. Male Wistar rats were divided into five groups: sham operated (SO), 5/6 nephrectomized (NFX), NFX + captopril (50 mg/ kg/day), NFX + losartan (10 mg/kg/day), and NFX + aliskiren (10 mg/kg/day). Animals were followed up for 60 days and protein urine excretion was measured. Systolic blood pressure, renal tissue RAS mRNA expression levels, plasma Ang II, and plasma Ang 1-7 were evaluated at day 60 after nephrectomy. Blood pressure and urine protein were increased after 5/6 nephrectomy. Ang II levels were increased 9.4 fold, whereas Ang 1-7 decreased 72.9% in NFX animals compared with SO rats. 5/6 nephrectomy increased renal angiotensinogen and (pro)renin receptor mRNA expression but down-regulated renin mRNA expression. RAS blockade restored the systolic blood pressure to normal values and slowed down urinary protein excretion, and also prevented changes in Ang II and Ang 1-7. RAS blockade reduced (pro)renin receptor, ACE, and AGT mRNA expression in the remnant kidney. However, renin mRNA expression increased compared with NFX rats. In conclusion these results suggest that inhibition of Ang II synthesis by RAS blockade is associated with renal regulation of RAS mRNA expression and this may be through a mechanism related with the Ang II/Ang 1-7 balance.

Ocular renin-angiotensin system with special reference in the anterior part of the eye

The renin-angiotensin system(RAS) regulates blood pressure(BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin Ⅱ, angiotensin converting enzyme 1 and angiotensin Ⅱ type 1 receptor(AngⅡ-ACE1-AT1R) together with angiotensin(1-7), angiotensin converting enzyme 2 and Mas receptor(Ang(1-7)-ACE2-Mas R) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory system accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngⅡ-ACE1-AT1 R and Ang(1-7)-ACE2-Mas R, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure(IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.

Renin angiotensin system in liver diseases: Friend or foe?

In the last three decades,the understanding of the renin angiotensin system(RAS)has been changed by the discoveries of functional local systems,novel biologically active peptides,additional specific receptors,alternative pathways of angiotensin(Ang)?Ⅱ?generation,and new roles for enzymes and precursor components other than those in Ang?Ⅱ?synthesis.In this regard,the discovery that Ang-(1-7)opposes the pressor,proliferative,pro-fibrotic,and pro-inflammatory effects mediated by Ang?Ⅱ?has contributed to the realization that the RAS is composed of two axes.The first axis consists of the angiotensin-converting enzyme(ACE),with Ang?Ⅱ?as the end product,and the angiotensin type 1(AT1)receptor as the main effector mediating the biological actions of Ang?Ⅱ.The second axis results from ACE2-mediated hydrolysis of Ang?Ⅱ,leading to the production of Ang-(1-7),with the Mas receptor as the main effector conveying the vasodilatory,antiproliferative,anti-fibrotic,and anti-inflammatory effects of Ang-(1-7).Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases.In this manuscript,we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications,including hemodynamic changes and hepatorenal syndrome.The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.

Serum levels of angiotensin converting enzyme as a biomarker of liver fibrosis

The renin angiotensin system(RAS) is classically conceived as a circulating hormonal system involved in blood pressure control and hydroelectrolyte balance. The discovery that RAS components are locally expressed in a wide range of organs and tissues,including the liver,pointed to a role for this system in the pathogenesis of several conditions including hepatic fibrosis and cirrhosis. It has been widely reported that the classical RAS axis composed by the angiotensin converting enzyme(ACE)-angiotensin(Ang) Ⅱ-Ang type 1(AT1) receptor mediates pro-inflammatory,pro-thrombotic,and pro-fibrotic processes. On the other hand,the alternative axis comprising ACE2-Ang-(1-7)-Mas receptor seems to play a protective role by frequently opposing Ang Ⅱ action. Chronic hepatitis B(CHB) is one of the leading causes of liver fibrosis,accounting for the death of nearly one million people worldwide. Liver fibrosis is a key factor to determine therapeutic interventions for patients with CHB. However,the establishment of non-invasive and accurate methods to detect reversible stages of liver fibrosis is still a challenge. In an elegant study published in the 36 th issue of the World Journal of Gastroenterology,Noguchi et al showed the predictive value of serum ACE levels in detecting not only advanced stages of liver fibrosis but also initial and intermediate fibrotic stages. The serum levels of ACE might represent an accurate,non-invasive,widely available,and easy method to evaluate fibrosis related to CHB. Moreover,therapies involving the inhibition of the classical RAS axis components might be promising in the control of CHB-related liver fibrosis.

Therapeutic potential of targeting the renin angiotensin system in portal hypertension

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet

AIM To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin-angiotensin system.METHODS Sprague-Dawley rats were fed with 8% NaCl high-salt （HS） or 0.4% NaCl （normal-salt, NS） diet for 3 wk, with or without tempol （T） （1 mmol/L, administered in drinking water）. Mean arterial pressure （MAP）, glomerular fltration rate （GFR）, and urinary sodium excretion （UVNa） were measured. We evaluated angiotensin Ⅱ （Ang Ⅱ）, angiotensin 1-7 （Ang 1-7）, angiotensin converting enzyme 2 （ACE2）, mas receptor （MasR）, angiotensin type 1 receptor （AT1R） and angiotensin type 2 receptor （AT2R） in renal tissues by immunohistochemistry.RESULTSThe intake of high sodium produced a slight but signifcant increase in MAP and differentially regulated components of the renal renin-angiotensin system （RAS）. This included an increase in Ang Ⅱ and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang Ⅱ and AT1R, as increase in AT2, ACE2, Ang （1-7） and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang （1-7） and MasR.CONCLUSION These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang Ⅱ. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS.

血管紧张素转换酶2-血管紧张素(1-7)-Mas轴的血压调控作用研究进展

近年来,随着人口老龄化的加剧,高血压的发病率呈现逐年增高的趋势。据WHO统计[1],全球约有1/3成年人患有高血压,我国每年由于高血压及其并发症死亡的人数占总死亡率的40%左右[2]。目前关于高血压的发生机制尚不十分清楚,一些研究认为与体液平衡、钠代谢、环境影响和家族遗传等因素有关[3-4]。自从1898年Tigerstedt等[5]发现肾素血管紧张素系统（renin angiotensin system,RAS）以来,其在调节血压、水盐代谢、血管张力、电解质平衡及调控心脏、肾脏功能等方面的生理作用逐渐被揭示出来[6]。RAS的主要成分由一系列的多肽组成，通过内分泌、旁分泌和自分泌方式调节心肌细胞、纤维细胞和血细胞功能，维持心血管系统平衡[7]。

Regression of cardiovascular remodeling in hypertension:Novel relevant mechanisms

Asymptomatic organ damage due to progressive kidney damage, cardiac hypertrophy and remodeling put hypertensive patients at high risk for developing heart and renal failure, myocardial infarction and stroke. Current antihypertensive treatment normalizes high blood pressure, partially reverses organ damage, and reduces the incidence of heart and renal failure. Activation of the renin-angiotensin system(RAS) is a primary mechanism of progressive organ damage and, specifically, a major cause of both renal and cardiovascular fibrosis. Currently, inhibition of the RAS system [mainly with angiotensin I converting enzyme inhibitors or angiotensin II(Ang II) receptor antagonists] is the most effective antihypertensive strategy for normalizing blood pressure and preventing target organ damage. However, residual organ damage and consequently high risk for cardiovascular events and renal failure still persist. Accordingly, in hypertension, it is relevant to develop new therapeutic perspectives, beyond reducing blood pressure to further prevent/reduce target organ damage by acting on pathways that trigger and maintain cardiovascular and renal remodeling. We review here relevant novel mechanisms of target organ damage in hypertension, their role and evidence in prevention/regression of cardiovascular remodeling and their possible clinical impact as well. Specifically, we focus on the signaling pathway Rho A/Rho kinase, on the impact of the vasodilatory peptides from the RAS and some insights on the role of estrogens and myocardial chymase in cardiovascular hypertensive remodeling.