MetaboLights
A nine amino acid peptide which is formed when angiotensin converting enzyme 2 (ACE2) hydrolyzes the carboxy terminal leucine from angiotensin I. It is a anti-cardiac hypertrophy agent.
Identification
L-alpha-aspartyl-L-arginyl-L-valyl-L-tyrosyl-L-isoleucyl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidine
[des-Leu(10)]-angiotensin I
ang-(1-9)
angiotensin I (1-9)
angiotensin-(1-9)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His
D-R-V-Y-I-H-P-F-H
des-Leu angiotensin I
DRVYIHPFH
L-Asp-L-Arg-L-Val-L-Tyr-L-Ile-L-His-L-Pro-L-Phe-L-His
Species
rattus norvegicus
NCBI:txid10116 26988149
homo sapiens
NCBI:txid9606 2170511
Europe PubMed Central results
Proton Pump Inhibitors in Pediatric Gastroesophageal Reflux Disease: A Systematic Review of Randomized Controlled Trials.
Author: Fernández-González SM, Moreno-Álvarez A, Solar-Boga A.
Abstract: This systematic review was conducted with the objective of understanding the efficacy and safety of proton pump inhibitors (PPIs) in the pediatric population. We used PubMed to identify randomized controlled trials (RCTs) published between 1 June 2010 and 30 June 2023, performed in patients from birth to 18 years old with gastroesophageal reflux disease (GERD) who received treatment with any PPI. This literature search yielded 76 articles and 13 of these met the inclusion criteria. For infants, PPIs were equal to placebos in reducing GERD symptoms in four articles. In one article, the numbers of GER episodes and esophageal acid exposures were lower in infants who received PPIs in the left lateral position, but there was generally no significant improvement in symptoms. In another publication, the combination of PPIs and feeding modifications (FMs) was not more effective than PPIs alone. For children and adolescents, PPIs were effective in improving symptoms and achieving endoscopic healing, which was subsequently maintained. To conclude, PPIs are not effective in reducing the symptoms related to GERD in infants but are effective in older children, where histological remission can be seen. Generally, PPIs are well tolerated, but it is important to remember the possible adverse events (AEs), especially if PPIs are used for an extended period.
Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism.
Author: Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM.
Abstract: In the RAS (renin-angiotensin system), Ang I (angiotensin I) is cleaved by ACE (angiotensin-converting enzyme) to form Ang II (angiotensin II), which has effects on blood pressure, fluid and electrolyte homoeostasis. We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin). The activity of the enzyme preparations was determined by active-site titrations using competitive tight-binding inhibitors and fluorogenic substrates. Ang I was effectively cleaved by NEP to Ang (1-7) (kcat/K(m) of 6.2x10(5) M(-1) x s(-1)), but was a poor substrate for ACE2 (kcat/K(m) of 3.3x10(4) M(-1) x s(-1)). Ang (1-9) was a better substrate for NEP than ACE (kcat/K(m) of 3.7x10(5) M(-1) x s(-1) compared with kcat/K(m) of 6.8x10(4) M(-1) x s(-1)). Ang II was cleaved efficiently by ACE2 to Ang (1-7) (kcat/K(m) of 2.2x10(6) M(-1) x s(-1)) and was cleaved by NEP (kcat/K(m) of 2.2x10(5) M(-1) x s(-1)) to several degradation products. In contrast with a previous report, Ang (1-7), like Ang I and Ang (1-9), was cleaved with a similar efficiency by both the N- and C-domains of ACE (kcat/K(m) of 3.6x10(5) M(-1) x s(-1) compared with kcat/K(m) of 3.3x10(5) M(-1) x s(-1)). The two active sites of ACE exhibited negative co-operativity when either Ang I or Ang (1-7) was the substrate. In addition, a range of ACE inhibitors failed to inhibit ACE2. These kinetic data highlight that the flux of peptides through the RAS is complex, with the levels of ACE, ACE2 and NEP dictating whether vasoconstriction or vasodilation will predominate.
DOI: 10.1042/bj20040634
Local formation of angiotensin peptides with paracrine activity by adipocytes.
Author: Weiland F, Verspohl EJ.
Abstract: A local paracrine angiotensin (ANG) system influences the insulin sensitivity and cell differentiation of adipose tissue. The limited view of a merely systemic renin-angiotensin-aldosterone-system with ANG II (1-8) as the main mediator of ANG-related effects may oversimplify the situation. The aim was to analyze the degradation of ANG by using capillary electrophoresis (CE) techniques. The supernatant of cultured 3T3-L1 adipocytes was used directly, and some data on degraded peptides were combined with a biological effect. The formation of several peptides such as ANG II (1-8), -III (2-8), -IV (3-8), and ANG (1-7) as degradation products is demonstrated; in addition low levels of ANG (3-7) are identified. The concentrations of the peptides ANG III (2-8) and ANG IV (3-8) (both are AT(4) receptor agonists) are modified in the vicinity of adipose tissue cells by amino-terminal degradation which resulted in ANG (3-8), -(4-8) and -(5-8). ANG IV (3-8) and ANG II (1-8) were biologically highly effective in inhibiting IRAP (insulin regulated aminopeptidase, part of the AT(4) receptor). It is observed that ANG (1-7) is the main degradation product derived from ANG I via ANG (1-9) and that ANG III (2-8) is one important regulated peptide for IRAP.
DOI: 10.1002/psc.1174
Angiotensin-(1-9) regulates cardiac hypertrophy in vivo and in vitro.
Author: Ocaranza MP, Lavandero S, Jalil JE, Moya J, Pinto M, Novoa U, Apablaza F, Gonzalez L, Hernandez C, Varas M, Lopez R, Godoy I, Verdejo H, Chiong M.
Abstract: <h4>Background</h4>Angiotensin-(1-9) is present in human and rat plasma and its circulating levels increased early after myocardial infarction or in animals treated with angiotensin-converting enzyme inhibitor. However, the cardiovascular effects of this peptide are unknown.<h4>Objective</h4>To determine whether angiotensin-(1-9) is a novel anti-cardiac hypertrophy factor in vitro and in vivo and whether this peptide is involved in the pharmacological effects of cardiovascular drugs acting on the renin-angiotensin system.<h4>Methods and results</h4>The administration of angiotensin-(1-9) to myocardial infarcted rats by osmotic minipumps (450 ng/kg per min, n = 6) vs. vehicle (n = 8) for 2 weeks decreased plasma angiotensin II levels, inhibited angiotensin-converting enzyme activity and also prevented cardiac myocyte hypertrophy. However, cardiac myocyte hypertrophy attenuation triggered by angiotensin-(1-9) was not modified with the simultaneous administration of the angiotensin-(1-7) receptor antagonist A779 (100 ng/kg per min, n = 6). In experiments in vitro with cultured cardiac myocytes incubated with norepinephrine (10 micromol/l) or with insulin-like growth factor-1 (10 nmol/l), angiotensin-(1-9) also prevented hypertrophy. In other experimental setting, myocardial infarcted rats (n = 37) were randomized to receive either vehicle (n = 12), enalapril (10 mg/kg per day, n = 12) or angiotensin II receptor blocker candesartan (10 mg/kg per day, n = 13) for 8 weeks. Both drugs prevented left ventricle hypertrophy and increased plasma angiotensin-(1-9) levels by several folds. Angiotensin-(1-9) levels correlated negatively with different left ventricular hypertrophy markers even after adjustment for blood pressure reduction.<h4>Conclusion</h4>Angiotensin-(1-9) is an effective and a novel anti-cardiac hypertrophy agent not acting via the Mas receptor.
Angiotensin-(1-9), the product of angiotensin I conversion in platelets, enhances arterial thrombosis in rats.
Author: Kramkowski K, Mogielnicki A, Leszczynska A, Buczko W.
Abstract: Angiotensin (Ang) (1-9) is the renin-angiotensin-system peptide found in the plasma of healthy volunteers and after angiotensin-converting-enzyme inhibitors therapy. In vitro experiments proved that Ang-(1-9) may be produced from Ang I. In our study, we tried to expand the poor data about the in vivo properties of Ang-(1-9). We revealed that Ang-(1-9) enhanced electrically stimulated arterial thrombosis in the carotid artery of Wistar rats. Losartan, a selective blocker of AT1 receptor for Ang II, abolished the prothrombotic activity of Ang-(1-9). This peptide increased plasma level of fibrinogen, augments fibrin generation, and similarly to Ang II, potentiated collagen induced platelet aggregation. Using HPLC, we found that after incubation of Ang-(1-9) with platelet homogenates or after intravenous administration this peptide is converted to Ang II. We concluded that Ang-(1-9) exerts an Ang II-like prothrombotic effect due to the conversion to Ang II in the circulatory system of rats and that platelets are involved in this process.
Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension.
Author: Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE.
Abstract: <h4>Background</h4>Angiotensin II (Ang II) levels depend on renin, angiotensin-converting enzyme (ACE), and on the homologous angiotensin-converting enzyme (ACE2). Increased ACE and Ang II levels are associated with higher Rho kinase activity. However, the relationship between Rho kinase activation and ACE2 in hypertension is unknown.<h4>Objective</h4>The role of the Rho kinase signaling pathway in both enzymatic activity and aortic gene expression of ACE2 in deoxycorticosterone acetate (DOCA) hypertensive rats was assessed in the present study.<h4>Methods and results</h4>Compared with sham animals, Rho kinase activity was higher by 400% (P<0.05) in the aortic wall of the DOCA hypertensive rats. In addition to blood pressure reduction, the specific Rho kinase inhibitor fasudil reduced aortic Rho kinase activity to levels observed in the sham control group and increased ACE2 enzymatic activity (by 83% in plasma and by 52% in the aortic wall, P<0.05), ACE2, and endothelial nitric oxide synthase (eNOS) aortic mRNA levels (by 340 and 40%, respectively, P<0.05) with respect to the untreated hypertensive DOCA rats. Fasudil also increased significantly plasma levels of Ang-(1-9) in normotensive and in the hypertensive rats. Aortic mRNA and protein levels of transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor 1 (PAI-1), and monocyte chemoattractant protein 1 (MCP-1) were significantly (P<0.05) higher in the untreated DOCA rats and were normalized by fasudil administration.<h4>Conclusion</h4>In experimental hypertension, Rho-associated, coiled-coil containing protein kinase (ROCK) inhibition reduces blood pressure and increases ACE2 levels and activity. At the same time, ROCK inhibition reduces angiotensin II and increases Ang-(1-9) plasma levels. Fasudil also increases vascular eNOS mRNA levels and reduces aortic overexpression of the remodeling promotion proteins TGF-β1, PAI-1, and MCP-1. This effect might additionally contribute to the antihypertensive and antiremodeling effects of ROCK inhibition in hypertension.
Probing the Druggablility on the Interface of the Protein-Protein Interaction and Its Allosteric Regulation Mechanism on the Drug Screening for the CXCR4 Homodimer.
Author: Shen L, Yuan Y, Guo Y, Li M, Li C, Pu X.
Abstract: Modulating protein-protein interactions (PPIs) with small drug-like molecules targeting it exhibits great promise in modern drug discovery. G protein-coupled receptors (GPCRs) are the largest family of targeted proteins and could form dimers in living biological cells through PPIs. However, compared to drug development of the orthosteric site, there has been lack of investigations on the druggability of the PPI interface for GPCRs and its functional implication on experiments. Thus, in order to address these issues, we constructed a novel computational strategy, which involved in molecular dynamics simulation, virtual screening and protein structure network (PSN), to study one representative GPCR homodimer (CXCR4). One druggable pocket was identified in the PPI interface and one small molecule targeting it was screened, which could strengthen PPI mainly through hydrophobic interaction between the benzene rings of the PPI molecule and TM4 of the receptor. The PSN results further reveals that the PPI molecule could increase the number of the allosteric regulation pathways between the druggable pocket of the dimer interface to the orthostatic site for the subunit A but only play minor role for the other subunit B, leading to the asymmetric change in the volume of the binding pockets for the two subunits (increase for the subunit A and minor change for the subunit B). Consequently, the screening performance of the subunit A to the antagonists is enhanced while the subunit B is unchanged nearly, implying that the PPI molecule may be beneficial to enhance the drug efficacies of the antagonists. In addition, one main regulation pathway with the highest frequency was identified for the subunit A, which consists of Trp195<sup>5.34</sup>-Tyr190<sup>ECL2</sup>-Val196<sup>5.35</sup>-Gln200<sup>5.39</sup>-Asp262<sup>6.58</sup>-Cys28<sup>N-term</sup>, revealing their importance in the allosteric regulation from the PPI molecule. The observations from the work could provide valuable information for the development of the PPI drug-like molecule for GPCRs.
Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor.
Author: Flores-Munoz M, Work LM, Douglas K, Denby L, Dominiczak AF, Graham D, Nicklin SA.
Abstract: The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (P<0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-l-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-l-arginine methyl ester=98.9±11.8%; control+N-nitro-l-arginine methyl ester=74.0±10.4%; P<0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the renin-angiotensin system.
Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor.
Author: Flores-Muñoz M, Godinho BM, Almalik A, Nicklin SA.
Abstract: The counter-regulatory axis of the renin angiotensin system peptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a potential therapeutic target in cardiac remodelling, acting via the mas receptor. Furthermore, we recently reported that an alternative peptide, Ang-(1-9) also counteracts cardiac remodelling via the angiotensin type 2 receptor (AT(2)R). Here, we have engineered adenoviral vectors expressing fusion proteins which release Ang-(1-7) [RAdAng-(1-7)] or Ang-(1-9) [RAdAng-(1-9)] and compared their effects on cardiomyocyte hypertrophy in rat H9c2 cardiomyocytes or primary adult rabbit cardiomyocytes, stimulated with angiotensin II, isoproterenol or arg-vasopressin. RAdAng-(1-7) and RAdAng-(1-9) efficiently transduced cardiomyocytes, expressed fusion proteins and secreted peptides, as demonstrated by western immunoblotting and conditioned media assays. Furthermore, secreted Ang-(1-7) and Ang-(1-9) inhibited cardiomyocyte hypertrophy (Control = 168.7±8.4 µm; AngII = 232.1±10.7 µm; AngII+RAdAng-(1-7) = 186±9.1 µm, RAdAng-(1-9) = 180.5±9 µm; P<0.05) and these effects were selectively reversed by inhibitors of their cognate receptors, the mas antagonist A779 for RAdAng-(1-7) and the AT(2)R antagonist PD123,319 for RAdAng-(1-9). Thus gene transfer of Ang-(1-7) and Ang-(1-9) produces receptor-specific effects equivalent to those observed with addition of exogenous peptides. These data highlight that Ang-(1-7) and Ang-(1-9) can be expressed via gene transfer and inhibit cardiomyocyte hypertrophy via their respective receptors. This supports applications for this approach for sustained peptide delivery to study molecular effects and potential gene therapeutic actions.
Angiotensin-(1-9) enhances stasis-induced venous thrombosis in the rat because of the impairment of fibrinolysis.
Author: Mogielnicki A, Kramkowski K, Hermanowicz JM, Leszczynska A, Przyborowski K, Buczko W.
Abstract: <h4>Introduction</h4>ACE2 alternatively converts angiotensin (Ang) II into Ang-(1-7) and Ang I into Ang-(1-9). There is little information in the literature with respect to Ang-(1-9) properties. A number of studies show a link between peptides of the renin-angiotensin system and thrombosis.<h4>Materials and methods</h4>We have investigated the influence of Ang-(1-9) on stasis-induced venous thrombosis in the rat. The contribution of coagulation and fibrinolytic systems, angiotensin receptor type 1 (AT1) and MAS receptor in the mode of Ang-(1-9) action was also determined.<h4>Results</h4>Ang-(1-9) enhanced thrombosis development, decreased plasma concentration of tissue plasminogen activator and increased the level of its inhibitor (PAI-1). The action of Ang-(1-9) was reversed by selective antagonist of AT1 receptor, but not Ang-(1-7) antagonist. Ang-(1-9) did not bind to the AT1 receptor.<h4>Conclusions</h4>Ang-(1-9) enhances venous thrombosis in the rat because of the impairment of fibrinolysis. The prothrombotic effect of Ang-(1-9) is mediated by Ang II acting via the AT1 receptor.
Stimulation of ANP by angiotensin-(1-9) via the angiotensin type 2 receptor.
Author: Cha SA, Park BM, Gao S, Kim SH.
Abstract: <h4>Aims</h4>Angiotensin-(1-9) [Ang-(1-9)] and Ang-(1-7) are cleaved by Ang converting enzyme 2 forming Ang I and Ang II, respectively, and the truncated Angs play a role in regulating atrial natriuretic peptide (ANP) secretion. Previously, we found that Ang-(1-7) stimulates ANP secretion via the Mas receptor. However, the effect of Ang-(1-9) on ANP secretion is still unknown. The aim of the present study is to determine whether Ang-(1-9) stimulates ANP secretion and to characterize the signaling pathway involved in stimulating secretion.<h4>Main methods</h4>We examined the effects of Ang-(1-9) on ANP secretion and atrial contractility with and without inhibitors in isolated perfused atria.<h4>Key findings</h4>Ang-(1-9) stimulated ANP secretion and concentration without change in atrial contractility. Ang-(1-9)-induced-ANP secretion was increased from 5% to 60% by 3 μM Ang-(1-9) during the low-stretch state of the atrium. This stimulatory effect of Ang-(1-9) on ANP secretion was attenuated by pretreatment with an Ang II type 2 receptor (AT2R) antagonist but not by AT1R or Mas receptor antagonist. In addition, pretreatment with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) blocked Ang-(1-9)-induced ANP secretion. In the high-stretch atrial state, Ang-(1-9)-induced ANP secretion was increased more than in the low-stretch state following addition of 1 μM Ang-(1-9) (from 108% to 170%). In an in vivo experiment, acute infusion of Ang-(1-9) increased plasma ANP level without altering arterial blood pressure. This effect was attenuated by pretreatment with AT2R antagonist but not by Mas receptor antagonist.<h4>Significance</h4>These results suggest that Ang-(1-9) stimulates ANP secretion via the AT2R-PI3K-Akt-NO-cGMP pathway.
Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis.
Author: Ocaranza MP, Moya J, Barrientos V, Alzamora R, Hevia D, Morales C, Pinto M, Escudero N, García L, Novoa U, Ayala P, Díaz-Araya G, Godoy I, Chiong M, Lavandero S, Jalil JE, Michea L.
Abstract: <h4>Background</h4>Little is known about the biological effects of angiotensin-(1-9), but available evidence shows that angiotensin-(1-9) has beneficial effects in preventing/ameliorating cardiovascular remodeling.<h4>Objective</h4>In this study, we evaluated whether angiotensin-(1-9) decreases hypertension and reverses experimental cardiovascular damage in the rat.<h4>Methods and results</h4>Angiotensin-(1-9) (600 ng/kg per min for 2 weeks) reduced already-established hypertension in rats with early high blood pressure induced by angiotensin II infusion or renal artery clipping. Angiotensin-(1-9) also improved cardiac (assessed by echocardiography) and endothelial function in small-diameter mesenteric arteries, cardiac and aortic wall hypertrophy, fibrosis, oxidative stress, collagen and transforming growth factor type β - 1 protein expression (assessed by western blot). The beneficial effect of angiotensin-(1-9) was blunted by coadministration of the angiotensin type 2(AT2) receptor blocker PD123319 (36 ng/kg per min) but not by coadministration of the Mas receptor blocker A779 (100 ng/kg per min). Angiotensin-(1-9) treatment also decreased circulating levels of Ang II, angiotensin-converting enzyme activity and oxidative stress in aorta and left ventricle. Whereas, Ang-(1-9) increased endothelial nitric oxide synthase mRNA levels in aorta as well as plasma nitrate levels.<h4>Conclusion</h4>Angiotensin-(1-9) reduces hypertension, ameliorates structural alterations (hypertrophy and fibrosis), oxidative stress in the heart and aorta and improves cardiac and endothelial function in hypertensive rats. These effects were mediated by the AT2 receptor but not by the angiotensin-(1-7)/Mas receptor axis.
Angiotensin-(1-7) and angiotensin-(1-9): function in cardiac and vascular remodelling.
Author: McKinney CA, Fattah C, Loughrey CM, Milligan G, Nicklin SA.
Abstract: The RAS (renin-angiotensin system) is integral to cardiovascular physiology; however, dysregulation of this system largely contributes to the pathophysiology of CVD (cardiovascular disease). It is well established that AngII (angiotensin II), the main effector of the RAS, engages the AT1R (angiotensin type 1 receptor) and promotes cell growth, proliferation, migration and oxidative stress, all processes which contribute to remodelling of the heart and vasculature, ultimately leading to the development and progression of various CVDs, including heart failure and atherosclerosis. The counter-regulatory axis of the RAS, which is centred on the actions of ACE2 (angiotensin-converting enzyme 2) and the resultant production of Ang-(1-7) [angiotensin-(1-7)] from AngII, antagonizes the actions of AngII via the receptor Mas, thereby providing a protective role in CVD. More recently, another ACE2 metabolite, Ang-(1-9) [angiotensin-(1-9)], has been reported to be a biologically active peptide within the counter-regulatory axis of the RAS. The present review will discuss the role of the counter-regulatory RAS peptides Ang-(1-7) and Ang-(1-9) in the cardiovascular system, with a focus on their effects in remodelling of the heart and vasculature.
DOI: 10.1042/cs20130436
Dissociating angiotensin 1-9 anticardiovascular remodeling effects from those on blood pressure.
Reply: dissociating angiotensin 1-9 anticardiovascular remodeling effects from those on blood pressure.
Author: Ocaranza MP, Michea L, Chiong M, Lavandero S, Jalil JE.
Abstract: NA
Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system.
Author: Ocaranza MP, Michea L, Chiong M, Lagos CF, Lavandero S, Jalil JE.
Abstract: Chronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro-hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT1R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1-9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by the AT2R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation.
DOI: 10.1042/cs20130449
Treatment with angiotensin-(1-9) alleviates the cardiomyopathy in streptozotocin-induced diabetic rats.
Author: Zheng H, Pu SY, Fan XF, Li XS, Zhang Y, Yuan J, Zhang YF, Yang JL.
Abstract: Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. We hypothesized that angiotensin-(1-9) [Ang-(1-9)] attenuates cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Rats were injected with a single intraperitoneal injection of STZ (55 mg/kg body weight) to induced diabetic cardiomyopathy. 4 weeks later, diabetic rats were treated with Ang-(1-9) (200 ng/kg/min), angiotensin type 2 receptor (AT2R) blocker PD123319 (100 ng/kg/min), or Mas antagonist A779 (100 ng/kg/min) for 4 weeks. Although Ang-(1-9) treatment did not affect blood glucose and insulin levels, it significantly attenuated cardiac hypertrophy, reduced cardiac fibrosis and improved ventricular function in STZ-induced diabetic rats. Ang-(1-9) treatment suppressed cardiac NADPH oxidase activity and reduced formation of reactive oxygen species. Ang-(1-9) suppressed NFκB activation and reduced myeloperoxidase (MPO) activity and mRNA levels of TNFα and IL-1β in hearts of diabetic rats. In addition, Ang-(1-9) treatment suppressed activity of ACE and reduced angiotensin II (Ang II) formation in hearts of diabetic rats. The beneficial effect of Ang-(1-9) was blunted by coadministration of PD123319 but not by coadministration of A779. Finally, it was found that Ang-(1-9) treatment could alleviate STZ-induced cardiomyopathy in a dose-dependent manner. In conclusions, Ang-(1-9) attenuates cardiac dysfunction in STZ-induced diabetic rats. The Ang-(1-9)/AT2R axis should be investigated as a novel target for treatment of type 1 diabetic cardiomyopathy.
Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9).
Author: Westermeier F, Bustamante M, Pavez M, García L, Chiong M, Ocaranza MP, Lavandero S.
Abstract: Insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) have been proposed to be important mediators in cardioprotection. A large body of evidence indicates that insulin like growth factor-1 has pleotropic actions in the heart (i.e., contractility, metabolism, hypertrophy, autophagy, senescence and cell death) and, conversely, its deficiency is associated with impaired cardiac function. Recently, we reported that insulin like growth factor-1 receptor is also located in plasma membrane invaginations with perinuclear localization, highlighting the role of nuclear Ca(2+) signaling in the heart. In parallel, angiotensin-(1-7) and angiotensin (1-9) acting through Mas receptor and angiotensin type 2 receptor have emerged as a novel anti-hypertensive molecules promoting vasodilatation and preventing heart hypertrophy. In this review we discuss the scientific evidence available regarding insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) in cardioprotection and its potential application as novel therapeutic targets for treating cardiac diseases.
Perindoprilat changes ANG (1-9) production in renal arteries isolated from young spontaneously hypertensive rats after ANG I incubation.
Author: Wołkow PP, Bujak-Giżycka B, Jawień J, Olszanecki R, Madej J, Rutowski J, Korbut R.
Abstract: We used mass spectrometry to quantitate production of angiotensinogen metabolites in renal artery of 3- and 7-month-old Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR). Tissue fragments were incubated for 15 min in oxygenated buffer, with added angiotensin I. Concentrations of angiotensins I (ANG I), II (ANG II), III (ANG III), IV (ANG IV), angiotensin (1-9) [ANG (1-9)], angiotensin (1-7) [ANG (1-7)], and angiotensin (1-5) [ANG (1-5)], excreted into the buffer during experiment, were measured using liquid chromatography-mass spectrometry (LC/MS) and expressed per mg of dry tissue. Effects of pretreatment with 10 microM perindoprilat on the production of ANG I metabolites were quantitated. Background production of any of ANG I metabolites differed neither between WKY and SHR rats nor between 3- and 7-month-old rats. Perindoprilat pretreatment of renal arteries resulted, as expected, in decrease of ANG II production. However, renal arteries of 7-month-old SHR rats were resistant to ACE inhibitor and did not change ANG II production in response to perindoprilat. In renal arteries, taken from 3-month-old rats, pretreated with perindoprilat, incubation with ANG I, resulted in the level of ANG (1-9) significantly higher in SHR than WKY rats. Our conclusion is that in SHR rats, sensitivity of renal artery ACE to perindoprilat inhibition changes with age.
Radioimmunoassay for immunoreactive [des-Leu10]-angiotensin I.
Author: Johnson H, Kourtis S, Waters J, Drummer OH.
Abstract: A specific radioimmunoassay for the angiotensin-derived peptide [des-Leu10]-angiotensin I (AI-dL) is described. Antisera obtained from rabbits injected with immunogen prepared by coupling bovine beta-thyroglobulin to the peptide with carbodiimide were specific to this peptide and did not recognise related angiotensin peptides such as AI, AII, AIII, nor did they recognise other peptides such as bradykinin, substance P, bombesin or dynorphin(1-8). Immunoreactive AI-dL was detected for the first time in the plasma of rats and humans following purification by HPLC at concentrations of 78 and 40 pg/ml, respectively. Concentrations of AI-dL are increased following chronic administration of captopril to rats.
Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.
Author: Fattah C, Nather K, McCarroll CS, Hortigon-Vinagre MP, Zamora V, Flores-Munoz M, McArthur L, Zentilin L, Giacca M, Touyz RM, Smith GL, Loughrey CM, Nicklin SA.
Abstract: <h4>Background</h4>Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).<h4>Objectives</h4>The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.<h4>Methods</h4>C57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.<h4>Results</h4>Gene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism.<h4>Conclusions</h4>Our novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A-dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.
Angiotensin-(1-9): New Promise for Post-Infarct Functional Therapy.
Angiotensin-(1-9) ameliorates pulmonary arterial hypertension <i>via</i> angiotensin type II receptor.
Author: Cha SA, Park BM, Kim SH.
Abstract: Angiotensin-(1-9) [Ang-(1-9)], generated from Ang I by Ang II converting enzyme 2, has been reported to have protective effects on cardiac and vascular remodeling. However, there is no report about the effect of Ang-(1-9) on pulmonary hypertension. The aim of the present study is to investigate whether Ang-(1-9) improves pulmonary vascular remodeling in monocrotaline (MCT)-induced pulmonary hypertensive rats. Sprague-Dawley rats received Ang-(1-9) (576 µg/kg/day) or saline via osmotic mini-pumps for 3 weeks. Three days after implantation of osmotic mini-pumps, 50 mg/kg MCT or vehicle were subcutaneously injected. MCT caused increases in right ventricular weight and systolic pressure, which were reduced by co-administration of Ang-(1-9). Ang-(1-9) also attenuated endothelial damage and medial hypertrophy of pulmonary arterioles as well as pulmonary fibrosis induced by MCT. The protective effects of Ang-(1-9) against pulmonary hypertension were inhibited by Ang type 2 receptor (AT<sub>2</sub>R) blocker, but not by Mas receptor blocker. Additionally, the levels of LDH and inflammatory cytokines, such as TNF-α, MCP-1, IL-1β, and IL-6, in plasma were lower in Ang-(1-9) co-treated MCT group than in vehicle-treated MCT group. Changes in expressions of apoptosis-related proteins such as Bax, Bcl-2, Caspase-3 and -9 in the lung tissue of MCT rats were attenuated by the treatment with Ang-(1-9). These results indicate that Ang-(1-9) improves MCT-induced pulmonary hypertension by decreasing apoptosis and inflammatory reaction <i>via</i> AT<sub>2</sub>R.
Protection of the myocardium against ischemia/reperfusion injury by angiotensin-(1-9) through an AT<sub>2</sub>R and Akt-dependent mechanism.
Author: Mendoza-Torres E, Riquelme JA, Vielma A, Sagredo AR, Gabrielli L, Bravo-Sagua R, Jalil JE, Rothermel BA, Sanchez G, Ocaranza MP, Lavandero S.
Abstract: Angiotensin-(19), a peptide of the non-classical renin angiotensin system, has been shown to prevent and revert hypertension and cardiac hypertrophy. We hypothetized that systemic delivery of angiotensin-(1-9) following myocardial infarction will also be protective and extend to provide protection during reperfusion of the ischemic heart. Adult Sprague Dawley rats were subjected to left anterior descending artery ligation and treated with angiotensin-(1-9) via osmotic mini-pump for 2 weeks in the presence or absence of Mas receptor or AT<sub>2</sub>R antagonists (A779 and PD123319, respectively). Myocardial death and left ventricular function were evaluated after infarction. Infarct size and functional parameters were determined in isolated rat hearts after global ischemia/reperfusion in the presence of angiotensin-(1-9) plus receptor antagonists or Akt inhibitor at reperfusion. in vitro, neonatal rat ventricular cardiomyocytes underwent simulated ischemia/reperfusion and angiotensin-(1-9) was co-incubated with A779, PD123319 or Akt inhibitor. Systemic delivery of angiotensin-(1-9) significantly decreased cell death and improved left ventricular recovery after in vivo myocardial infarction. Perfusion with the peptide reduced the infarct size and improved functional recovery after ex vivo ischemia/reperfusion. In vitro, angiotensin-(1-9) decreased cell death in isolated neonatal rat ventricular cardiomyocytes subjected to simulated ischemia/reperfusion. The cardioprotective effects of angiotensin-(1-9) were blocked by PD123319 and Akti VIII but not by A779. Angiotensin-(1-9) limits reperfusion-induced cell death by an AT<sub>2</sub>R- and Aktdependent mechanism. Angiotensin-(1-9) is a novel strategy to protect against cardiac ischemia/reperfusion injury.
Angiotensin-(1-9) reduces cardiovascular and renal inflammation in experimental renin-independent hypertension.
Author: Gonzalez L, Novoa U, Moya J, Gabrielli L, Jalil JE, García L, Chiong M, Lavandero S, Ocaranza MP.
Abstract: Hypertension-induced cardiovascular and renal damage can be mediated by activation of the renin-angiotensin-aldosterone system. There are different factors beyond renin-angiotensin-aldosterone system involved in hypertension and renal damage. Inflammation has emerged as an important mediator of hypertension and cardiovascular and kidney damage. Angiotensin-(1-9), a peptide of the renin-angiotensin system, counter-regulates both the physiological and pathological actions of angiotensin II. Recent data has shown that angiotensin-(1-9) protects the heart and blood vessels from adverse cardiovascular remodeling in experimental models of hypertension and/or heart failure and reduces cardiac fibrosis in stroke-prone, spontaneously hypertensive rats. These effects are mediated by the angiotensin II type 2 receptor (AT2R). However, it remains unknown whether angiotensin-(1-9) also has an anti-inflammatory effect. In the present study, we investigate whether angiotensin-(1-9) reduces inflammation and fibrosis in the heart, arteries, and kidney in a DOCA-salt hypertensive model and explore the mechanisms underlying the amelioration of end-organ damage. DOCA-salt hypertensive rats received: a) vehicle, b) angiotensin-(1-9), c) PD123319 (AT2R blocker), d) angiotensin-(1-9) plus A779 (a Mas receptor blocker) or e) angiotensin-(1-9) plus PD123319, and sham rats were used as a control. Our results showed that angiotensin-(1-9) decreased hypertension and increased vasodilation in DOCA-salt hypertensive rats. These actions were partially inhibited by PD123319. Moreover, angiotensin-(1-9) decreased diuresis, fibrosis, and inflammation. These beneficial effects were not mediated by Mas or AT2R blockers. We concluded that angiotensin-(1-9) protects against volume overload-induced hypertensive cardiovascular and kidney damage by decreasing inflammation in the heart, aortic wall, and kidney, through mechanisms independent of the Mas or AT2R.
The opposite effects of angiotensin 1-9 and angiotensin 3-7 in prostate epithelial cells.
Author: Domińska K, Kowalska K, Habrowska-Górczyńska DE, Urbanek KA, Ochędalski T, Piastowska-Ciesielska AW.
Abstract: There is growing evidence that renin-angiotensin system (RAS) components have been involved in the development of various types of cancers, including prostate cancer. This article for the first time reports the impact of Ang1-9 and Ang3-7 on viability and proliferation, migration and invasion of epithelial prostate cells. The results of this study clearly show that Ang1-9 and Ang3-7 exert different/opposite effects on in vitro biological properties of prostate cells. It appears that Ang1-9 has pro-cancer activities via the ability to induce cell divisions, enhance cell motility and stimulate the expression of such genes as vascular endothelial growth factor (VEGF), hypoxia-inducible factors (HIF-1), vimentin (VIM) and REL proto-oncogene, NF-kB subunit (REL). On the contrary, Ang3-7 did not show any mitogenic activity. Furthermore, this peptide hormone limited the migration of PNT1A cells probably by downregulation of VEGF and VIM expression. Finally, it is worth noting that both angiotensins have the ability to modulate gene expression for angiotensin receptors. Unfortunately, we could not unequivocally identify the type of angiotensin receptor responsible for signal transduction pathway involved in PNT1A cell survival and proliferation. Undoubtedly, further research and testing in this area are necessary.
Angiotensin-(1-9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway.
Author: Sotomayor-Flores C, Rivera-Mejías P, Vásquez-Trincado C, López-Crisosto C, Morales PE, Pennanen C, Polakovicova I, Aliaga-Tobar V, García L, Roa JC, Rothermel BA, Maracaja-Coutinho V, Ho-Xuan H, Meister G, Chiong M, Ocaranza MP, Corvalán AH, Parra V, Lavandero S.
Abstract: Angiotensin-(1-9) is a peptide from the noncanonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. In the present study we aimed to elucidate it, basing us initially on previous work from our group and colleagues who proved a relationship between disturbances in mitochondrial morphology and calcium handling, associated with the setting of cardiac hypertrophy. Our first finding was that angiotensin-(1-9) can induce mitochondrial fusion through DRP1 phosphorylation. Secondly, angiotensin-(1-9) blocked mitochondrial fission and intracellular calcium dysregulation in a model of norepinephrine-induced cardiomyocyte hypertrophy, preventing the activation of the calcineurin/NFAT signaling pathway. To further investigate angiotensin-(1-9) anti-hypertrophic mechanism, we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1-9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that PKA activity is necessary for the effects of angiotensin-(1-9) over mitochondrial dynamics, calcium handling and its anti-hypertrophic effects.