Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions

The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supporting a role for the renin-angiotensin system in the lung tumor microenvironment and discusses whether blockade of this pathway in clinical settings may serve as an adjuvant therapy in lung cancer.

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Differential Effects of Doxazosin on Renin-Angiotensin-System- Regulating Aminopeptidase Activities in Neuroblastoma and Glioma Tumoral Cells

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666181029111739 ◽

2019 ◽

Vol 18 (1) ◽

pp. 29-36 ◽

Cited By ~ 4

Author(s):

María Jesús Ramírez-Expósito ◽

José Manuel Martínez-Martos

Keyword(s):

Cell Proliferation ◽

Cell Growth ◽

Cell Lines ◽

Renin Angiotensin System ◽

Human Neuroblastoma ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

Tumoral Cell ◽

Specific Activities

Background: It has been described that doxazosin, an antihypertensive drug, also promotes glioblastoma cells death by inhibiting cell proliferation, arresting cell cycle and inducing apoptosis. Doxazosin has also demonstrated several modulator effects on renin-angiotensin system (RAS)- regulating aminopeptidase activities, which are highly involved in tumor growth in experimental glioma. Therefore, it remains to elucidate if the anti-tumoral effects of doxazosin could also be mediated by the proteolytic regulatory components of the RAS. Objective: To analyze the effects of doxazosin on cell growth and on RAS-regulating proteolytic regulatory aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase N (APN), aminopeptidase B (APB) and insulin-regulated aminopeptidase (IRAP) specific activities in the human neuroblastoma NB69 and astroglioma U373-MG tumoral cell lines. Methods: Human neuroblastoma NB69 and astroglioma U373-MG cell lines were treated with doxazosin 50-500 μM for 24h or 48h. The effects on cell growth and on RAS-regulating aminopeptidase specific activities were analyzed. Results: Doxazosin treatments promote a concentration-dependent inhibition on cell growth in both NB69 and U373-MG cells, being NB69 cells more sensitive to the drug than U373-MG cells. However, its effects on RAS-regulating aminopeptidase specific activities depend on the concentration used, the duration of the treatment and the cell type. These data confirm the existence of a different dynamic progression of RAS cascade in each tumoral cell line as a consequence of the treatment with doxazosin and time of action, which also implies a very dynamic metabolism of the peptides which participate in each step of RAS cascade. Conclusion: Our results indicate that doxazosin modifies the proteolytic regulatory enzymes of RAS cascade, modulating the bioactive efficacy of the different angiotensin peptides, and therefore, of their functional roles as initiators/promoters of cell proliferation as autocrine/paracrine mediators.

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The Biochemical Effects of Angiotensin-(1-7) on the Oxidative Stress Metabolism and Their Specific Parameters from the Temporal Lobe

Revista de Chimie ◽

10.37358/rc.20.6.8196 ◽

2020 ◽

Vol 71 (6) ◽

pp. 307-311

Author(s):

Sorin Ungurianu ◽

Constantin Trus ◽

Roxana-Rosmary Enciu

Keyword(s):

Oxidative Stress ◽

Temporal Lobe ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

Vascular Area ◽

Ang Iv ◽

The One

It is already known from a variety of previous reports that an independent brain renin�angiotensin system (RAS) exists, completely separated from the one in the periphery. This independent brain RAS has all the precursors and the enzymatic structures necessary for the generation of the angiotensin peptides. Thus, in the last few years various groups started focusing on the more central effects of less known angiotensins (e.g in comparison with Angiotensin (Ang) II), namely Ang III, Ang IV, Ang-(1�7) or Ang 5-8. One of these newly emerging angiotensins which has become an increased center of interest in many studies is Ang-(1-7), which is a heptapeptide previously described especially for its opposite effects to Ang II, in the peripheral vascular area, but also described for some opposite central functions vs. Ang II. These aspects are completed with the fact that it was recently suggested that the renin�angiotensin system could modulate the oxidative stress metabolism, and also it seems that the manifestations of Angiotensin-(1-7) on the basal oxidative stress status are contradictory, with a variety of reports describing controversial (e.g. both pro-oxidant and antioxidant actions) effects for this heptapeptide. Our results presented here are confirming a possible antioxidant effect of Ang-(1�7) administration on rat, as shown by the increased levels of antioxidant enzymes from the temporal lobe (superoxide dismutase and glutathione peroxidase) and decreased levels of malondialdehyde, as an important lipid peroxidation parameter.

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The renin-angiotensin system: going beyond the classical paradigms

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00723.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. H958-H970 ◽

Cited By ~ 61

Author(s):

Robson Augusto Souza Santos ◽

Gavin Y. Oudit ◽

Thiago Verano-Braga ◽

Giovanni Canta ◽

Ulrike Muscha Steckelings ◽

...

Keyword(s):

Renin Angiotensin System ◽

Protective Effects ◽

Ang Ii ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Amino Terminal ◽

Angiotensin Peptides ◽

Protective Actions

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1−7) [ANG-(1−7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT2R), in contrast to the other, the ANG II type 1 receptor (AT1R), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1−7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled “The Renin-Angiotensin System: Going Beyond the Classical Paradigms,” in which the signaling and physiological actions of ANG-(1−7), ACE2, AT2R, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.

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Contribution of circulating renin to local synthesis of angiotensin peptides in the heart

Physiological Genomics ◽

10.1152/physiolgenomics.2000.4.1.67 ◽

2000 ◽

Vol 4 (1) ◽

pp. 67-73 ◽

Cited By ~ 33

Author(s):

GARY PRESCOTT ◽

DAVID W. SILVERSIDES ◽

SUI MEI LINDA CHIU ◽

TIMOTHY L. REUDELHUBER

Keyword(s):

Blood Pressure ◽

Cardiac Fibrosis ◽

Direct Evidence ◽

Renin Angiotensin System ◽

Local Synthesis ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

Specific Synthesis

The activity of a local cardiac renin-angiotensin system (RAS) has long been suspected in the promotion of cardiac pathologies including hypertrophy, ischemia, and infarction. All of the components of the RAS cascade have been demonstrated to be synthesized within the heart with the possible exception of the first enzyme in the cascade, renin. In the current study, we provide direct evidence that circulating renin can contribute to cardiac-specific synthesis of angiotensin peptides. Furthermore, we demonstrate this effect is independent of blood pressure and that in animals of comparable blood pressure, elevated circulating renin significantly enhances cardiac fibrosis. These results may serve to explain some of the cardiac pathologies associated with the RAS.

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Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00618.2015 ◽

2016 ◽

Vol 310 (2) ◽

pp. H137-H152 ◽

Cited By ~ 108

Author(s):

Mark C. Chappell

Keyword(s):

Renin Angiotensin System ◽

Cellular Growth ◽

Receptor Subtypes ◽

Ang Ii ◽

Angiotensin System ◽

Physiological Regulation ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

The Status ◽

Biochemical Evaluation

The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure through peripheral and central mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacological blockade of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) offers an effective therapeutic regimen. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-ANG II-AT1R axis that promotes vasoconstriction; water intake; sodium retention; and increased oxidative stress, fibrosis, cellular growth, and inflammation. In contrast, the nonclassical RAS composed primarily of the ANG II/ANG III-AT2R and the ACE2-ANG-(1–7)-AT7R pathways generally opposes the actions of a stimulated ANG II-AT1R axis. In lieu of the complex and multifunctional aspects of this system, as well as increased concerns on the reproducibility among laboratories, a critical assessment is provided on the current biochemical approaches to characterize and define the various components that ultimately reflect the status of the RAS.

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Abstract 387: Individual Biochemical Characterization of the Renin-Angiotensin-System by RAS-Fingerprinting in Healthy Volunteers Treated with RAS-Blockers

Hypertension ◽

10.1161/hyp.60.suppl_1.a387 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Marko Poglitsch ◽

Cornelia Schwager ◽

Oliver Domenig ◽

Dunja van Oyen ◽

Manfred Schuster ◽

...

Keyword(s):

Healthy Volunteers ◽

Whole Blood ◽

Biochemical Characterization ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Patient Specific ◽

Angiotensin System ◽

Renin Angiotensin ◽

Associated Diseases ◽

Angiotensin Peptides

The Renin-Angiotensin-System (RAS) is critically involved in the regulation of important physiological functions including blood pressure and fluid balance. It is constituted by multiple enzymes giving rise to a meshwork of effector peptides, which mediate their functions through binding to specific receptor molecules. Therefore, the modification of angiotensin peptide levels represents a common strategy for the treatment of RAS-associated diseases and is frequently achieved by the pharmacologic regulation of enzymes taking part in angiotensin metabolism. We developed a highly sensitive method, which allows the simultaneous absolute quantification of up to 10 different angiotensin peptides in human plasma and whole blood (RAS-Fingerprinting). The measurement of RAS-Fingerprints provides unique insights into the physiology of the human RAS and therefore represents a powerful tool for the patient specific evaluation of this physiologically important peptide hormone system. Beside the precise quantification of angiotensin peptides in plasma and whole blood, RAS-Fingerprints analyze the biochemical hardware of the RAS at a previously unachieved level of detail and accuracy. During the development and validation of our LC-MS/MS based method, comprehensive datasets showing multiple applications for RAS-Fingerprinting have been generated. Investigation of healthy volunteers revealed that a patient specific state of the RAS exists, which is defined by a unique composition of RAS enzyme activities that might have crucial effects on the outcome of RAS targeted therapies in individual patients. RAS-Fingerprinting in healthy volunteers treated with an Angiotensin-Receptor-Blockers, ACE-Inhibitor or Renin-Inhibitor revealed that the human RAS reacts to different drugs in a very dynamic and specific way. Therefore, RAS-Fingerprinting could contribute to the development of innovative therapeutic approaches affecting the RAS. The implementation of RAS-Fingerprinting into clinical studies would substantially enhance our understanding of the human RAS and could lead to the development of personalized treatment schemes in the management of RAS-associated diseases in the near future.

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Regulation of endothelial proliferation by the renin–angiotensin system in human umbilical vein endothelial cells

Reproduction ◽

10.1530/rep-07-0374 ◽

2008 ◽

Vol 136 (1) ◽

pp. 125-130 ◽

Cited By ~ 35

Author(s):

D Herr ◽

M Rodewald ◽

H M Fraser ◽

G Hack ◽

R Konrad ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Endothelial Cells ◽

Angiotensin Ii ◽

Umbilical Vein ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Human Umbilical Vein ◽

Renin Angiotensin ◽

Umbilical Vein Endothelial Cells

This study was performed in order to evaluate the role of angiotensin II in physiological angiogenesis. Human umbilical vein endothelial cells (HUVEC) were stained for angiotensin II type 1 receptor (AGTR1) immunocytochemically and for gene expression of renin–angiotensin system (RAS) components. The regulation of the angiogenesis-associated genes vascular endothelial growth factor (VEGF) and angiopoietins (ANGPT1andANGPT2) were studied using quantitative RT-PCR. Furthermore, we examined the effect of angiotensin II on the proliferation of HUVEC using Ki-67 as well as BrdU immunocytochemistry and investigated whether the administration of the AGTR1 blocker candesartan or the VEGF antagonist FLT1-Fc could suppress the observed angiotensin II-dependent proangiogenic effect. AGTR1 was expressed in HUVEC and the administration of angiotensin II significantly increased the gene expression ofVEGFand decreased the gene expression ofANGPT1. Since the expression ofANGPT2was not affected significantly the ratio of ANGPT1/ANGPT2 was decreased. In addition, a significantly increased endothelial cell proliferation was observed after stimulation with angiotensin II, which was suppressed by the simultaneous administration of candesartan or the VEGF antagonist FLT1-Fc. These results indicate the potential capacity of angiotensin II in influencing angiogenesis by the regulation of angiogenesis-associated genes via AGTR1. Since VEGF blockade opposed the effect of angiotensin II on cell proliferation, it is hypothesised that VEGF mediates the angiotensin II-dependent effect in concert with the changes in angiopoietin expression. This is the first report of the RAS on the regulation of angiogenesis-associated genes in physiology.

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The Influence of Angiotensin Peptides on Survival and Motility of Human High-Grade Serous Ovarian Cancer Cells in Serum Starvation Conditions

International Journal of Molecular Sciences ◽

10.3390/ijms23010052 ◽

2021 ◽

Vol 23 (1) ◽

pp. 52

Author(s):

Kamila Domińska ◽

Kinga Anna Urbanek ◽

Karolina Kowalska ◽

Dominika Ewa Habrowska-Górczyńska ◽

Marta Justyna Kozieł ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Renin Angiotensin System ◽

G1 Phase ◽

Ovarian Cancer Cells ◽

Serum Starvation ◽

High Grade ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides

High-grade serous ovarian carcinoma (HGSOC) is the most frequent and malignant form of ovarian cancer. A local renin–angiotensin system (RAS) has been found in the ovary, and changes in selected components of this system were observed in pathological states and also in ovarian cancer. In the present study, we examined the effect of three peptides, Ang-(1-7), Ang-(1-9) and Ang-(3-7), on proliferation and motility of the OVPA8 cell line, a new well-defined and preclinical model of HGSOC. We confirmed the presence of mRNA for all angiotensin receptors in the tested cells. Furthermore, our findings indicate that all tested angiotensin peptides increased the metabolic serum in the medium by activation of cell defense mechanisms such as nuclear factor kappaB signaling pathway andapoptosis. Moreover, tested angiotensin peptides intensified serum starvation-induced cell cycle arrest at the G0/G1 phase. In the case of Ang-(3-7), a significant decrease in the number of Ki67 positive cells (Ki67+) and reduced percentage of activated ERK1/2 levels in ovarian cancer cells were additionally reported. The angiotensin-induced effect of the accumulation of cells in the G0/G1 phase was not observed in OVPA8 cells growing on the medium with 10% FBS. Moreover, in the case of Ang-(3-7), the tendency was quite the opposite. Ang-(1-7) but not Ang-(1-9) or Ang-(3-7) increased the mobility of reluctant-to-migrate OVAP8 cells cultured in the serum-free medium. In any cases, the changes in the expression of VIM and HIF1A gene, associated with epithelial–mesenchymal transition (EMT), were not observed. In conclusion, we speculate that the adaptation to starvation in nutrient-deprived tumors can be modulated by peptides from the renin–angiotensin system. The influence of angiotensin peptides on cancer cells is highly dependent on the availability of growth factors and nutrients.

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Abstract 421: Cardiac Hypertrophy Induced by Swimming Exercise in Mice and the Cardiac Renin-Angiotensin System: The More, the Better?

Circulation Research ◽

10.1161/res.121.suppl_1.421 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Santiago Alonso L Tobar ◽

Douglas S Soares ◽

Graziela H Pinto ◽

Daniel S Caetano ◽

Amanda Lopes ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Renin Angiotensin System ◽

Angiotensin Receptors ◽

Swimming Training ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

Physiological Cardiac Hypertrophy ◽

Wide Range

Cardiac hypertrophy is an adaptive process which is triggered by different mechanism in order to improve blood flow to organism and it may progress as physiological or pathological. Physical exercise offers a wide range hemodynamic stimulus; consequently it may modulate several molecular mechanisms associated to cardiac hypertrophy, for instance the local cardiac renin-angiotensin system (RAS). Thus, the aim of this study was to analyze the classical (ANGII/AT1) and alternative (ANG1-7/MAS) axis of the RAS in the cardiac muscle of mice submitted to exercise with different volumes/intensity training for the development of cardiac hypertrophy. Therefore, male Balb/c mice were divided in three groups: (i) Sedentary (SED), (ii) swimming training twice a day (T2), and (iii) swimming training three times a day with 2% of body weight overload (T3), for six weeks of training. The cardiac hypertrophy was assessed by the left ventricle weight and tibial length (LV/mm) ratio and cardiomyocytes cross-sectional area. Angiotensin peptides were analyzed by HPLC and angiotensin receptor measured by western blotting. We have also analyzed fibrosis by masson’s tricrome and the fetal genes reactivation was assessed by qRT-PCR. Both swimming training induced cardiac hypertrophy, the CHI for groups was T2 (6.34±0.44 mg/mm) and T3 (6.74 ± 0.70 mg/mm) compared to SED (5.55±0.5 mg/mm, p = 0.002). There was no observed change in the levels of angiotensin peptides ANG-I, ANG-II, and ANG1-7 between training groups and sedentary, however when we analyze angiotensin receptors, group T3 showed higher levels of AT1 when compared to SED (p=0.004), while MASR levels was higher in T2 compared to SED (0.017). Further, there was moderate reactivation of fetal genes as evidenced by increased in MHC-β expression observed in T3, but without fibrosis in either group. Our results suggest that increasing volumes/intensity of exercise beyond moderate does not influence the magnitude or the structural phenotype of physiological cardiac hypertrophy. However, it might promote the activation of molecular mechanisms involved in pathological cardiac hypertrophy.

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An Intracellular Renin-Angiotensin System in Neurons: Fact, Hypothesis, or Fantasy

Physiology ◽

10.1152/physiol.00002.2008 ◽

2008 ◽

Vol 23 (4) ◽

pp. 187-193 ◽

Cited By ~ 102

Author(s):

Justin L. Grobe ◽

Di Xu ◽

Curt D. Sigmund

Keyword(s):

Renin Angiotensin System ◽

Biosynthetic Pathways ◽

Angiotensin System ◽

Renin Angiotensin ◽

Angiotensin Peptides ◽

Physiological Processes ◽

The Brain

The renin-angiotensin system in the brain acts to regulate a number of physiological processes. Evidence suggests that angiotensin peptides may act as neurotransmitters, although their biosynthetic pathways are poorly understood. We review evidence for neuronal production of angiotensin peptides and hypothesize that angiotensin may be synthesized intracellularly in neurons.

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