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Renin Kinetics Are Superior to Lactate Kinetics for Predicting In-Hospital Mortality in Hypotensive Critically Ill Patients. Crit Care Med 2021; 50:50-60. [PMID: 34166293 DOI: 10.1097/ccm.0000000000005143] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Whole blood lactate concentration is widely used in shock states to assess perfusion. We aimed to determine if the change in plasma renin concentration over time would be superior to the change in lactate concentration for predicting in-hospital mortality in hypotensive patients on vasopressors. DESIGN Prospective, observational cohort study. SETTING Tertiary academic ICU. PATIENTS Adult patients on vasopressors for greater than 6 hours to maintain a mean arterial pressure greater than or equal to 65 mm Hg during January 2020. INTERVENTIONS Plasma renin concentrations were measured at enrollment and at 24, 48, and 72 hours. Whole blood lactate measurements were performed according to normal standard of care. Logistic regression was performed to evaluate whether the change in renin or lactate concentration could predict in-hospital mortality. Generalized estimating equations were used to analyze the association between renin and lactate concentration and in-hospital mortality. The area under the receiver operating characteristics curve was performed to measure the discriminative ability of initial and peak renin and lactate concentration to predict mortality. The association between renin and lactate concentration above the upper limit of normal at each timepoint with in-hospital mortality was also examined. MEASUREMENTS AND MAIN RESULTS The study included 197 renin and 148 lactate samples obtained from 53 patients. The slope of the natural log (ln) of renin concentration was independently associated with mortality (adjusted odds ratio, 10.35; 95% CI, 1.40-76.34; p = 0.022), but the slope of ln-lactate concentration was not (adjusted odds ratio, 4.78; 95% CI, 0.03-772.64; p = 0.55). The generalized estimating equation models found that both ln-renin (adjusted odds ratio, 1.18; 95% CI, 1.02-1.37; p = 0.025) and ln-lactate (adjusted odds ratio, 2.38; 95% CI, 1.05-5.37; p = 0.037) were associated with mortality. Area under the receiver operating characteristics curve analysis demonstrated that initial renin could predict in-hospital mortality with fair discrimination (area under the receiver operating characteristics curve, 0.682; 95% CI, 0.503-0.836; p = 0.05), but initial lactate could not (area under the receiver operating characteristics curve, 0.615; 95% CI, 0.413-0.803; p = 0.27). Peak renin (area under the receiver operating characteristics curve, 0.728; 95% CI, 0.547-0.888; p = 0.01) and peak lactate (area under the receiver operating characteristics curve, 0.746; 95% CI, 0.584-0.876; p = 0.01) demonstrated moderate discrimination. There was no significant difference in discriminative ability between initial or peak renin and lactate concentration. At each study time point, a higher proportion of renin values exceeded the threshold of normal (40 pg/mL) in nonsurvivors than in survivors, but this association was not significant for lactate. CONCLUSIONS Although there was no significant difference in the performance of renin and lactate when examining the absolute values of each laboratory, a positive rate of change in renin concentration, but not lactate concentration, over 72 hours was associated with in-hospital mortality. For each one-unit increase in the slope of ln-renin, the odds of mortality increased 10-fold. Renin levels greater than 40 pg/mL, but not lactate levels greater than 2 mmol/L, were associated with in-hospital mortality. These findings suggest that plasma renin kinetics may be superior to lactate kinetics in predicting mortality of hypotensive, critically ill patients.
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The Role of Angiotensin Antagonism in Coronary Plaque Regression: Insights from the Glagovian Model. Int J Vasc Med 2021; 2021:8887248. [PMID: 33880191 PMCID: PMC8046567 DOI: 10.1155/2021/8887248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 03/21/2021] [Indexed: 11/17/2022] Open
Abstract
The benefit of antagonizing the effect of the renin angiotensin aldosterone system (RAAS), notably by the use of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor blocker (ARB) for coronary artery disease (CAD), has been demonstrated in multiple studies, which may be attributed to their ability to inhibit the deleterious effect of RAAS to the cardiovascular system. It is well known that angiotensin II (Ang II) plays a vital role in atheromatous plaque formation and progression through multiple pathways, including inflammatory and arterial remodeling aspects. Significant coronary atheromatous plaque regression has been previously demonstrated in various studies using statin agents. Similar results have been reported in different studies using angiotensin inhibitor agents, notably ARB agents. Analysis from various trials utilizing ARB showed a significant plaque regression using olmesartan and telmisartan as evaluated by IVUS studies. In contrary, the use of ACEi did not demonstrated significant plaque regression, which may be attributed to the heavy plaque calcification in respective studies. On this review, we aim to present the basic mechanism on the role of RAAS in plaque modulation and its arterial remodeling aspect, which is then integrated with the clinical evidence based on the available intravascular ultrasonography (IVUS) studies on coronary arteries.
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Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II-Renin Feedback in Hypertensive Patients. Int J Hypertens 2021; 2020:6653851. [PMID: 33489354 PMCID: PMC7803135 DOI: 10.1155/2020/6653851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 12/10/2020] [Indexed: 11/17/2022] Open
Abstract
Objectives Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. Methods A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II-renin feedback were assessed. Results After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group (p < 0.05) than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels (p < 0.05), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1-7) (Ang-(1-7)) to angiotensin II in plasma than the amlodipine group (p < 0.05). Conclusions The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1-7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.
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Holappa M, Vapaatalo H, Vaajanen A. Local ocular renin-angiotensin-aldosterone system: any connection with intraocular pressure? A comprehensive review. Ann Med 2020; 52:191-206. [PMID: 32308046 PMCID: PMC7877937 DOI: 10.1080/07853890.2020.1758341] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/15/2020] [Indexed: 12/28/2022] Open
Abstract
The renin-angiotensin system (RAS) is one of the oldest and most extensively studied human peptide cascades, well-known for its role in regulating blood pressure. When aldosterone is included, RAAS is involved also in fluid and electrolyte homeostasis. There are two main axes of RAAS: (1) Angiotensin (1-7), angiotensin converting enzyme 2 and Mas receptor (ACE2-Ang(1-7)-MasR), (2) Angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor (ACE1-AngII-AT1R). In its entirety, RAAS comprises dozens of angiotensin peptides, peptidases and seven receptors. The first mentioned axis is known to counterbalance the deleterious effects of the latter axis. In addition to the systemic RAAS, tissue-specific regulatory systems have been described in various organs, evidence that RAAS is both an endocrine and an autocrine system. These local regulatory systems, such as the one present in the vascular endothelium, are responsible for long-term regional changes. A local RAAS and its components have been detected in many structures of the human eye. This review focuses on the local ocular RAAS in the anterior part of the eye, its possible role in aqueous humour dynamics and intraocular pressure as well as RAAS as a potential target for anti-glaucomatous drugs.KEY MESSAGESComponents of renin-angiotensin-aldosterone system have been detected in different structures of the human eye, introducing the concept of a local intraocular renin-angiotensin-aldosterone system (RAAS).Evidence is accumulating that the local ocular RAAS is involved in aqueous humour dynamics, regulation of intraocular pressure, neuroprotection and ocular pathology making components of RAAS attractive candidates when developing new effective ways to treat glaucoma.
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Affiliation(s)
- Mervi Holappa
- Medical Faculty, Department of Pharmacology, University of Helsinki, Helsinki, Finland
| | - Heikki Vapaatalo
- Medical Faculty, Department of Pharmacology, University of Helsinki, Helsinki, Finland
| | - Anu Vaajanen
- Department of Ophthalmology, Helsinki University Hospital, Helsinki, Finland
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Haspula D, Clark MA. Molecular Basis of the Brain Renin Angiotensin System in Cardiovascular and Neurologic Disorders: Uncovering a Key Role for the Astroglial Angiotensin Type 1 Receptor AT1R. J Pharmacol Exp Ther 2018; 366:251-264. [PMID: 29752427 DOI: 10.1124/jpet.118.248831] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/08/2018] [Indexed: 12/13/2022] Open
Abstract
The central renin angiotensin system (RAS) is one of the most widely investigated cardiovascular systems in the brain. It is implicated in a myriad of cardiovascular diseases. However, studies from the last decade have identified its involvement in several neurologic abnormalities. Understanding the molecular functionality of the various RAS components can thus provide considerable insight into the phenotypic differences and mechanistic drivers of not just cardiovascular but also neurologic disorders. Since activation of one of its primary receptors, the angiotensin type 1 receptor (AT1R), results in an augmentation of oxidative stress and inflammatory cytokines, it becomes essential to investigate not just neuronal RAS but glial RAS as well. Glial cells are key homeostatic regulators in the brain and are critical players in the resolution of overt oxidative stress and neuroinflammation. Designing better and effective therapeutic strategies that target the brain RAS could well hinge on understanding the molecular basis of both neuronal and glial RAS. This review provides a comprehensive overview of the major studies that have investigated the mechanisms and regulation of the brain RAS, and it also provides insight into the potential role of glial AT1Rs in the pathophysiology of cardiovascular and neurologic disorders.
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Affiliation(s)
- Dhanush Haspula
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin (D.H.); and College of Pharmacy, Department of Pharmaceutical Sciences, Nova Southeastern University, Ft. Lauderdale, Florida (M.A.C.)
| | - Michelle A Clark
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin (D.H.); and College of Pharmacy, Department of Pharmaceutical Sciences, Nova Southeastern University, Ft. Lauderdale, Florida (M.A.C.)
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Holappa M, Vapaatalo H, Vaajanen A. Many Faces of Renin-angiotensin System - Focus on Eye. Open Ophthalmol J 2017; 11:122-142. [PMID: 28761566 PMCID: PMC5510558 DOI: 10.2174/1874364101711010122] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 05/17/2017] [Accepted: 05/25/2017] [Indexed: 12/18/2022] Open
Abstract
The renin-angiotensin system (RAS), that is known for its role in the regulation of blood pressure as well as in fluid and electrolyte homeostasis, comprises dozens of angiotensin peptides and peptidases and at least six receptors. Six central components constitute the two main axes of the RAS cascade. Angiotensin (1-7), an angiotensin converting enzyme 2 and Mas receptor axis (ACE2-Ang(1-7)-MasR) counterbalances the harmful effects of the angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor axis (ACE1-AngII-AT1R) Whereas systemic RAS is an important factor in blood pressure regulation, tissue-specific regulatory system, responsible for long term regional changes, that has been found in various organs. In other words, RAS is not only endocrine but also complicated autocrine system. The human eye has its own intraocular RAS that is present e.g. in the structures involved in aqueous humor dynamics. Local RAS may thus be a target in the development of new anti-glaucomatous drugs. In this review, we first describe the systemic RAS cascade and then the local ocular RAS especially in the anterior part of the eye.
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Affiliation(s)
- Mervi Holappa
- BioMediTech, University of Tampere, Tampere, Finland
| | - Heikki Vapaatalo
- Medical Faculty, Department of Pharmacology, University of Helsinki, 00014 Helsinki, Finland
| | - Anu Vaajanen
- Department of Ophthalmology, Tampere University Hospital, Tampere, Finland.,SILK, Department of Ophthalmology, School of Medicine, University of Tampere, Tampere, Finland
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Preu J, Tiefenauer L, Gutberlet T. Adhesion ability of angiotensin II with model membranes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2016; 1859:195-200. [PMID: 27865700 DOI: 10.1016/j.bbamem.2016.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 11/14/2016] [Accepted: 11/15/2016] [Indexed: 01/08/2023]
Abstract
The octa-peptide angiotensin II (Ang II, (H2NAspArgValTyrIleHisProPheCOOH)) is one of the key player on blood pressure regulation in mammals. Predominantly binding to the Angiotensin type 1 and 2 receptors, the hormone is one of several peptide ligands binding to G protein coupled receptors (GPCR). The active hormone derives from a high molecular weight precursor sequentially cleaved by the proteases renin and the angiotensin converting enzyme (ACE). The chemical nature of the amino acid sequence has an impact on the behavior in the proximity of membranes, demonstrated using different membrane model systems and biophysical methods. Applying electrochemical impedance spectroscopy and small angle X-ray scattering a detailed view on the adhesion of the peptide with model membrane surfaces was performed. The role of specific amino acids involved in the interaction with the phospholipid head group were investigated and, studying a truncated version of Ang II, Ang (1-7), the key role of the C-terminal phenylalanine was proven. Truncation of the C-terminal amino acid abolishes the binding of the peptide to the membrane surface. A shift in pH, altering the protonation state of the central histidine residue impairs the adhesion of Ang II.
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Affiliation(s)
- Julia Preu
- Membrane Biophysics Group, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
| | - Louis Tiefenauer
- Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland
| | - Thomas Gutberlet
- Jülich Centre for Neutron Science at Heinz Maier-Leibnitz Zentrum, Forschungszentrum Jülich GmbH, Garching, Germany
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Ferrario CM, Ahmad S, Varagic J, Cheng CP, Groban L, Wang H, Collawn JF, Dell Italia LJ. Intracrine angiotensin II functions originate from noncanonical pathways in the human heart. Am J Physiol Heart Circ Physiol 2016; 311:H404-14. [PMID: 27233763 PMCID: PMC5008653 DOI: 10.1152/ajpheart.00219.2016] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 05/26/2016] [Indexed: 12/11/2022]
Abstract
Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.
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Affiliation(s)
- Carlos M Ferrario
- Departments of Surgery, Internal Medicine-Nephrology and Physiology-Pharmacology, Wake Forest University Health Science Center, Winston-Salem, North Carolina;
| | - Sarfaraz Ahmad
- Departments of Surgery, Internal Medicine-Nephrology and Physiology-Pharmacology, Wake Forest University Health Science Center, Winston-Salem, North Carolina
| | - Jasmina Varagic
- Departments of Surgery, Internal Medicine-Nephrology and Physiology-Pharmacology, Wake Forest University Health Science Center, Winston-Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest University Health Science Center, Winston-Salem, North Carolina
| | - Che Ping Cheng
- Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University Health Science Center, Winston-Salem, North Carolina
| | - Leanne Groban
- Hypertension and Vascular Research Center, Wake Forest University Health Science Center, Winston-Salem, North Carolina; Department of Anesthesiology, Wake Forest University Health Science Center, Winston-Salem, North Carolina
| | - Hao Wang
- Department of Anesthesiology, Wake Forest University Health Science Center, Winston-Salem, North Carolina
| | - James F Collawn
- Departments of Cell Biology, Microbiology, Physiology, University of Alabama Birmingham, Alabama; and
| | - Louis J Dell Italia
- Departments of Cell Biology, Microbiology, Physiology, University of Alabama Birmingham, Alabama; and Division of Cardiovascular Disease, University of Alabama at Birmingham and Department of Veterans Affairs, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
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Ferrario CM, VonCannon J, Jiao Y, Ahmad S, Bader M, Dell'Italia LJ, Groban L, Varagic J. Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene. Am J Physiol Heart Circ Physiol 2016; 310:H995-1002. [PMID: 26873967 DOI: 10.1152/ajpheart.00833.2015] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/08/2016] [Indexed: 12/12/2022]
Abstract
Angiotensin-(1-12) [ANG-(1-12)] is processed into ANG II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human ANG-(1-12) render the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin-dependent effects of increased hAGT expression on heart function and arterial pressure. Compared with Sprague-Dawley (SD) control rats (n= 11), male homozygous TGR(hAGT)L1623 (n= 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human ANG-(1-12) immunofluorescence within myocytes of TGR(hAGT)L1623 rats was associated with a fourfold increase in cardiac ANG II content. Chymase enzymatic activity, using the rat or human ANG-(1-12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac angiotensin-converting enzyme (ACE) and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular ANG II content might be a product of an increased cardiac expression of ANG II generated through a non-renin-dependent mechanism. The data also underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function.
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Affiliation(s)
- Carlos M Ferrario
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Departments of Medicine-Nephrology and Physiology-Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Jessica VonCannon
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Yan Jiao
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Sarfaraz Ahmad
- Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Michael Bader
- Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
| | - Louis J Dell'Italia
- Division of Cardiovascular Disease, University of Alabama at Birmingham and Department of Veterans Affairs, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
| | - Leanne Groban
- Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, North Carolina; and
| | - Jasmina Varagic
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Departments of Medicine-Nephrology and Physiology-Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina
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Holappa M, Vapaatalo H, Vaajanen A. Ocular renin-angiotensin system with special reference in the anterior part of the eye. World J Ophthalmol 2015; 5:110-124. [DOI: 10.5318/wjo.v5.i3.110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/21/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
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-MasR) 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 systems 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-AT1R and Ang(1-7)-ACE2-MasR, 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.
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Ribeiro AA, Palomino Z, Lima MP, Souza LE, Ferreira DS, Pesquero JB, Irigoyen MC, Pesquero JL, Casarini DE. Characterization of the renal renin-angiotensin system in transgenic mice that express rat tonin. J Renin Angiotensin Aldosterone Syst 2015. [PMID: 26216430 DOI: 10.1177/1470320315595572] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Tonin is an enzyme that is able to generate angiotensin II (Ang II) from angiotensin I (Ang I) or directly from angiotensinogen. Our goal was to characterize the renal renin-angiotensin system in transgenic mice that express rat tonin (TGM`(rTon)). MATERIALS AND METHODS Mice were euthanized and the kidneys removed for analysis. Tonin activity was evaluated by radioimmunoassay and angiotensin I-converting enzyme (ACE) activity by HPLC. Tonin, ACE and angiotensin II-converting enzyme (ACE2) expression was analyzed by Western blotting. RESULTS Tonin activity was significantly increased in TGM`(rTon) compared to their respective wild-type (WT) littermates (1.7 ± 0.21 vs 0.11 ± 0.02 nmol of Ang II/min/mg of protein). Tonin activity had a strong positive correlation with tonin expression in both TGM`(rTon) and their respective wild-type littermates. The ACE activity and expression levels of 65-kDa N-domain angiotensin I-converting enzyme isoform were significantly increased in the TGM`(rTon) when compared with WT. ACE2 expression levels were statistically significantly higher in the TGM`(rTon) when compared with WT. Angiotensin 1-7 (Ang(1-7)) and Ang I levels were significantly lower in the TGM`(rTon). CONCLUSIONS We suggest that the environment of tonin abundance may increase N-domain ACE activity liberated by a secretase able to cleave somatic ACE.
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Affiliation(s)
- Amanda A Ribeiro
- Department of Medicine, Nephrology Division, Universidade Federal de São Paulo, Escola Paulista de Medicina, Brazil
| | - Zaira Palomino
- Department of Medicine, Nephrology Division, Universidade Federal de São Paulo, Escola Paulista de Medicina, Brazil
| | - Mércia P Lima
- Department of Basic Nursing, Nursing School, Universidade Federal de Minas Gerais, Brazil
| | - Leandro E Souza
- Heart Institute, Medical School of University of São Paulo, Brazil
| | | | - João B Pesquero
- Department of Biophysics, Universidade Federal de São Paulo, Brazil
| | - Maria C Irigoyen
- Heart Institute, Medical School of University of São Paulo, Brazil
| | - Jorge L Pesquero
- Department of Biophysics, Universidade Federal de Minas Gerais, Brazil
| | - Dulce E Casarini
- Department of Medicine, Nephrology Division, Universidade Federal de São Paulo, Escola Paulista de Medicina, Brazil
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Wagenaar GTM, Sengers RMA, Laghmani EH, Chen X, Lindeboom MPHA, Roks AJM, Folkerts G, Walther FJ. Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats. Am J Physiol Lung Cell Mol Physiol 2014; 307:L261-72. [PMID: 24951776 DOI: 10.1152/ajplung.00345.2013] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg·kg(-1)·day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 μg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg·kg(-1)·day(-1)) in two models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2-3 and PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.
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Affiliation(s)
- Gerry T M Wagenaar
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
| | - Rozemarijn M A Sengers
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands
| | - El Houari Laghmani
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Xueyu Chen
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Melissa P H A Lindeboom
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Anton J M Roks
- Division of Vascular Disease and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Gert Folkerts
- Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; and
| | - Frans J Walther
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California
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Varagic J, Ahmad S, Nagata S, Ferrario CM. ACE2: angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury. Curr Hypertens Rep 2014; 16:420. [PMID: 24510672 PMCID: PMC4286874 DOI: 10.1007/s11906-014-0420-5] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent in this interactive biochemical cascade. Over the last decade, angiotensin-converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1-7). This review addresses the considerable advancement in research on the role of tissue ACE2 in the development and progression of hypertension and cardiac and renal injury. We summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. We also review recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1-7) axis.
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Affiliation(s)
- Jasmina Varagic
- Hypertension & Vascular Research Center, Division of Surgical Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA,
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Suski M, Olszanecki R, Stachowicz A, Madej J, Bujak-Giżycka B, Okoń K, Korbut R. The influence of angiotensin-(1–7) Mas receptor agonist (AVE 0991) on mitochondrial proteome in kidneys of apoE knockout mice. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:2463-9. [DOI: 10.1016/j.bbapap.2013.08.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 08/19/2013] [Indexed: 12/18/2022]
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Kawabe T, Kawabe K, Sapru HN. Cardiovascular effect of angiotensin-(1-12) in the caudal ventrolateral medullary depressor area of the rat. Am J Physiol Heart Circ Physiol 2013; 306:H438-49. [PMID: 24285114 DOI: 10.1152/ajpheart.00628.2013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Angiotensin (ANG)-(1-12) excites neurons via ANG II type 1 receptors (AT1Rs), which are present in the caudal ventrolateral medullary depressor area (CVLM). We hypothesized that microinjections of ANG-(1-12) into the CVLM may elicit decreases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity. This hypothesis was tested in urethane-anesthetized adult male Wistar rats. Microinjections of ANG-(1-12) into the CVLM elicited decreases in MAP, HR, and greater splanchnic nerve activity (GSNA). ANG-(1-12)-induced responses consisted of initial (first 1-8 min) and delayed (8-24 min) phases. Prior microinjections of losartan, A-779, and captopril into the CVLM blocked initial, delayed, and both phases of ANG-(1-12) responses, respectively. Blockade of GABA receptors in the rostral ventrolateral medullary pressor area (RVLM) attenuated cardiovascular responses elicited by microinjections of ANG-(1-12) into the ipsilateral CVLM. Microinjections of ANG-(1-12) into the CVLM potentiated the reflex decreases and attenuated the reflex increases in GSNA elicited by intravenous injections of phenylephrine and sodium nitroprusside, respectively. These results indicate that microinjections of ANG-(1-12) into the CVLM elicit decreases in MAP, HR, and GSNA. Initial and delayed phases of these responses are mediated via ANG II and ANG-(1-7), respectively; the effects of ANG II and ANG-(1-7) are mediated via AT1Rs and Mas receptors, respectively. Captopril blocked both phases of ANG-(1-12) responses, indicating that angiotensin-converting enzyme is important in mediating these responses. GABA receptors in the RVLM partly mediate the cardiovascular responses to microinjections of ANG-(1-12) into the CVLM. Microinjections of ANG-(1-12) into the CVLM modulate baroreflex responses.
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Affiliation(s)
- Tetsuya Kawabe
- Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, New Jersey
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Abstract
SIGNIFICANCE The renin-angiotensin system (RAS) plays an important role in the normal control of cardiovascular and renal function in the healthy state and is a contributing factor in the development and progression of various types of cardiovascular diseases (CVD), including hypertension, diabetes, and heart failure. RECENT ADVANCES Evidence suggests that a balance between activation of the ACE/Ang II/AT1 receptor axis and the ACE2/Ang-(1-7)/Mas receptor axis is important for the function of the heart, kidney, and autonomic nervous system control of the circulation in the normal healthy state. An imbalance in these opposing pathways toward the ACE/Ang II/AT1 receptor axis is associated with CVD. The key component of this imbalance with respect to neural control of the circulation is the negative interaction between oxidative and NO• mechanisms, which leads to enhanced sympathetic tone and activation in disease conditions such as hypertension and heart failure. CRITICAL ISSUES The key mechanisms that disrupt normal regulation of Ang II and Ang-(1-7) signaling and promote pathogenesis of CVD at all organ levels remain poorly understood. The reciprocal relation between ACE and ACE2 expression and function suggests they are controlled interdependently at pre- and post-translational levels. Insights from neural studies suggest that an interaction between oxidative and nitrosative pathways may be key. FUTURE DIRECTIONS The role of redox mechanisms in the control of expression and activity of RAS enzymes and Ang receptors may provide important insight into the function of local tissue RAS in health and disease.
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Affiliation(s)
- Kaushik P Patel
- 1 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center , Omaha, Nebraska
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Moniwa N, Varagic J, Simington SW, Ahmad S, Nagata S, Voncannon JL, Ferrario CM. Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism. Am J Physiol Heart Circ Physiol 2013; 305:H644-50. [PMID: 23812388 DOI: 10.1152/ajpheart.00210.2013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol·kg(-1)·min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme.
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Affiliation(s)
- Norihito Moniwa
- Division of Surgical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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Wagenaar GTM, Laghmani EH, Fidder M, Sengers RMA, de Visser YP, de Vries L, Rink R, Roks AJM, Folkerts G, Walther FJ. Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2013; 305:L341-51. [PMID: 23812633 DOI: 10.1152/ajplung.00360.2012] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 μg·kg(-1)·day(-1)] and AT2 [dKcAng-(1-7); 5-20 μg·kg(-1)·day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester (25 mg·kg(-1)·day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.
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Affiliation(s)
- Gerry T M Wagenaar
- Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, the Netherlands.
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Impurity identification and determination for the peptide hormone angiotensin I by liquid chromatography–high-resolution tandem mass spectrometry and the metrological impact on value assignments by amino acid analysis. Anal Bioanal Chem 2013; 405:8039-51. [DOI: 10.1007/s00216-013-6953-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 03/25/2013] [Accepted: 03/27/2013] [Indexed: 10/26/2022]
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Botelho-Santos GA, Bader M, Alenina N, Santos RAS. Altered regional blood flow distribution in Mas-deficient mice. Ther Adv Cardiovasc Dis 2013; 6:201-11. [PMID: 23045193 DOI: 10.1177/1753944712461164] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND We have recently shown that the acute infusion of angiotensin-(1-7) [Ang-(1-7)] or chronic increase in plasma Ang-(1-7) produces important changes in regional blood flow in rats. METHODS To further assess whether these changes are related to Mas, in this study hemodynamic measurements were performed in Ang-(1-7) receptor Mas knockout C57BL/6 (Mas-KO) mice and age-matched wild type (WT) control mice, using fluorescent microspheres. RESULTS Mean arterial pressure in urethane-anesthetized Mas-KO mice (12-16 weeks old) did not differ from that in WT mice (79 ± 2 and 80 ± 2 mmHg respectively). However, pronounced differences were observed in other hemodynamic measurements. Mas-KO mice exhibited a significant decrease in stroke volume (0.03 ± 0.01 versus 0.05 ± 0.01 ml/beat in WT) and decreased cardiac index (0.81 ± 0.08 versus 1.24 ± 0.24 ml/min/g in WT). Strikingly, Mas-KO mice exhibited a marked increase in vascular resistance and a decrease in blood flow in the kidney, lung, adrenal gland, mesentery, spleen and brown fat tissue. The decrease in blood flow ranged from 34% (spleen) to 55% (brown fat tissue). CONCLUSION These results suggest that the Ang-(1-7)/Mas axis plays an important role in regional and systemic hemodynamic adjustments in mice.
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Affiliation(s)
- Giancarla Aparecida Botelho-Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, ICBUFMG, Minas Gerais, Brazil
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Uehara Y, Fujimi K, Yahiro E, Abe S, Devarajan S, Saku K, Urata H. Induction of tissue angiotensin II-forming activity in two-kidney, one-clip hypertensive hamster model. World J Hypertens 2013; 3:9. [DOI: 10.5494/wjh.v3.i2.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 08/09/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
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Krishnan B, Torti FM, Gallagher PE, Tallant EA. Angiotensin-(1-7) reduces proliferation and angiogenesis of human prostate cancer xenografts with a decrease in angiogenic factors and an increase in sFlt-1. Prostate 2013; 73:60-70. [PMID: 22644934 DOI: 10.1002/pros.22540] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Accepted: 04/20/2012] [Indexed: 12/27/2022]
Abstract
BACKGROUND Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. The purpose of this study was to determine the anti-proliferative and anti-angiogenic efficacy of angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone, in human prostate cancer xenografts. METHODS Human LNCaP prostate cancer cells were injected into the flank of athymic mice and tumors were treated with Ang-(1-7) for 54 days. Tumor growth and angiogenesis were determined by immunohistochemistry and western blot hybridization. RESULTS Ang-(1-7) markedly reduced the volume and wet weight of LNCaP xenograft tumors. Histological analysis of tumor sections from saline-treated mice showed increased Ki67 immunoreactivity and enhanced phosphorylation of the MAP kinases ERK1/2 compared to tumors from Ang-(1-7)-treated mice, suggesting that the heptapeptide reduces cell proliferation. Intratumoral vessel density was decreased in Ang-(1-7)-treated mice with an associated reduction in vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), suggesting that the heptapeptide attenuates vascularization by reducing angiogenic factors. Ang-(1-7) administration markedly increased the soluble fraction of VEGF receptor 1 (sFlt-1), with a concomitant reduction in VEGF receptors 1 and 2. sFlt-1 serves as a decoy receptor that traps VEGF and PlGF, making the ligands unavailable to membrane-bound VEGF receptors and preventing activation of pro-angiogenic signaling. CONCLUSIONS The decrease in PlGF and VEGF coupled with the increase in sFlt-1 suggests that Ang-(1-7) may serve as a novel anti-angiogenic therapy for prostate cancer. Further, the pleiotropic mechanisms of action by Ang-(1-7) may limit angiogenic resistance that occurs with VEGF inhibitors or receptor blockers.
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Affiliation(s)
- Bhavani Krishnan
- Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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23
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Sapru HN. Role of the hypothalamic arcuate nucleus in cardiovascular regulation. Auton Neurosci 2012; 175:38-50. [PMID: 23260431 DOI: 10.1016/j.autneu.2012.10.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 10/16/2012] [Accepted: 10/18/2012] [Indexed: 02/07/2023]
Abstract
Recently the hypothalamic arcuate nucleus (Arc) has been implicated in cardiovascular regulation. Both pressor and depressor responses can be elicited by the chemical stimulation of the Arc. The direction of cardiovascular responses (increase or decrease) elicited from the Arc depends on the baseline blood pressure. The pressor responses are mediated via increase in sympathetic nerve activity and involve activation of the spinal ionotropic glutamate receptors. Arc-stimulation elicits tachycardic responses which are mediated via inhibition of vagal input and excitation of sympathetic input to the heart. The pathways within the brain mediating the pressor and tachycardic responses elicited from the Arc have not been delineated. The depressor responses to the Arc-stimulation are mediated via the hypothalamic paraventricular nucleus (PVN). Gamma aminobutyric acid type A receptors, neuropeptide Y1 receptors, and opiate receptors in the PVN mediate the depressor responses elicited from the Arc. Some circulating hormones (e.g., leptin and insulin) may reach the Arc via the leaky blood-brain barrier and elicit their cardiovascular effects. Although the Arc is involved in mediating the cardiovascular responses to intravenously injected angiotensin II and angiotensin-(1-12), these effects may not be due to leakage of these peptides across the blood-brain barrier in the Arc; instead, circulating angiotensins may act on neurons in the SFO and mediate cardiovascular actions via the projections of SFO neurons to the Arc. Cardiovascular responses elicited by acupuncture have been reported to be mediated by direct and indirect projections of the Arc to the RVLM.
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Affiliation(s)
- Hreday N Sapru
- Department of Neurological Surgery, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.
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Lee TC, Greene-Schloesser D, Payne V, Diz DI, Hsu FC, Kooshki M, Mustafa R, Riddle DR, Zhao W, Chan MD, Robbins ME. Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res 2012; 178:46-56. [PMID: 22687052 PMCID: PMC3422865 DOI: 10.1667/rr2731.1] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 mg/L of ramipril in the drinking water starting 3 days before irradiation, or (4) fractionated whole-brain irradiation plus ramipril. Cognitive function was assessed using a perirhinal cortex-dependent version of the novel object recognition task 26 weeks after irradiation. Microglial activation was determined in the perirhinal cortex and the dentate gyrus of the hippocampus 28 weeks after irradiation using the ED1 antibody. Neurogenesis was assessed in the granular cell layer and subgranular zones of the dentate gyrus using a doublecortin antibody. Fractionated whole-brain irradiation led to: (1) a significant impairment in perirhinal cortex-dependent cognitive function, (2) a significant increase in activated microglia in the dentate gyrus but not in the perirhinal cortex, and (3) a significant decrease in neurogenesis. Continuous administration of ramipril before, during, and after irradiation prevented the fractionated whole-brain irradiation-induced changes in perirhinal cortex-dependent cognitive function, as well as in microglial activation in the dentate gyrus. Thus, as hypothesized, continuous administration of the angiotensin-converting enzyme inhibitor, ramipril, can prevent the fractionated whole-brain irradiation-induced impairment in perirhinal cortex-dependent cognitive function.
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Affiliation(s)
- Tammy C Lee
- Department of Molecular Medicine and Translational Science, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA
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Mason RP. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2012. [DOI: 10.15829/1728-8800-2012-3-102-112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Cardiovascular (CV) disease is a major factor in mortality rates around the world and contributes to more than one-third of deaths in the US. The underlying cause of CV disease is atherosclerosis, a chronic inflammatory process that is clinically manifested as coronary artery disease, carotid artery disease, or peripheral artery disease. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Consequently, developing a treatment regimen that can slow or even reverse the atherosclerotic process is imperative. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with CV risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. Since the renin– angiotensin–aldosterone system (RAAS) plays a key role in vascular inflammatory responses, hypertension treatment with RAAS-blocking agents (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers [ARBs]) may slow inflammatory processes and disease progression. Reduced nitric oxide (NO) bioavailability has an important role in the process of endothelial dysfunction and hypertension. Therefore, agents that increase NO and decrease oxidative stress, such as ARBs and ACEIs, may interfere with atherosclerosis. Studies show that angiotensin II type 1 receptor antagonism with an ARB improves endothelial function and reduces atherogenesis. In patients with hypertension, the ARB olmesartan medoxomil provides effective blood pressure lowering, with inflammatory marker studies demonstrating significant RAAS suppression. Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS). Although CV outcomes were not assessed in these studies, the observed benefits in surrogate endpoints of disease suggest that RAAS suppression with olmesartan medoxomil may potentially have beneficial effects on CV outcomes in these patient populations.
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Sukumaran V, Veeraveedu PT, Gurusamy N, Lakshmanan AP, Yamaguchi K, Ma M, Suzuki K, Nagata M, Takagi R, Kodama M, Watanabe K. Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor. Mol Cell Endocrinol 2012; 351:208-19. [PMID: 22200414 DOI: 10.1016/j.mce.2011.12.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 12/09/2011] [Accepted: 12/12/2011] [Indexed: 11/23/2022]
Abstract
Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.
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Affiliation(s)
- Vijayakumar Sukumaran
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
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Komatsu Y, Kida N, Nozaki N, Kuwasako K, Nagata S, Kitamura K, Kato J. Effects of proangiotensin-12 infused continuously over 14 days in conscious rats. Eur J Pharmacol 2012; 683:186-9. [PMID: 22414812 DOI: 10.1016/j.ejphar.2012.02.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 02/13/2012] [Accepted: 02/26/2012] [Indexed: 01/13/2023]
Abstract
The carboxyl terminal-extended form of angiotensin I, proangotensin-12, was recently identified in rat tissues including the small intestine, cardiac ventricles, and kidneys. Single administration of proangiotensin-12 exerts vasoconstrictor and pressor effects, probably by conversion to angiotensin II; however, there are currently no data available about the subacute effects of proangiotensin-12. In the present study, we examined the effects of prolonged infusion of proangiotensin-12 in conscious rats. Continuous, subcutaneous infusion of 240 pmol/kg/min of proangiotensin-12 gradually elevated blood pressure over 14 days, as did the same dose of angiotensin II. The pressor effects of proangiotensin-12 were abolished by oral administration of losartan, an angiotensin II type 1 receptor blocker, or perindopril, an angiotensin converting enzyme (ACE) inhibitor. Meanwhile, angiotensin II-induced elevation of blood pressure was inhibited by losartan but not by perindopril. Both the plasma aldosterone level and heart weight/body weight ratio were increased by the prolonged infusion of proangiotensin-12, but these increases were attenuated by losartan and perindopril. The present results suggest that proangiotensin-12 infused continuously over 14 days exerts pressor effects accompanied with the elevation of plasma aldosterone and cardiac hypertrophy in an ACE- and angiotensin II type 1 receptor-dependent manner.
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Affiliation(s)
- Yoichi Komatsu
- Department of Nutrition Science, Minami Kyusyu University, Miyazaki 880-0032, Japan
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Angiotensin-(1-7)-mediated signaling in cardiomyocytes. Int J Hypertens 2012; 2012:493129. [PMID: 22518286 PMCID: PMC3303610 DOI: 10.1155/2012/493129] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 11/22/2011] [Accepted: 11/24/2011] [Indexed: 01/20/2023] Open
Abstract
The Renin-Angiotensin System (RAS) acts at multiple targets and has its synthesis machinery present in different tissues, including the heart. Actually, it is well known that besides Ang II, the RAS has other active peptides. Of particular interest is the heptapeptide Ang-(1-7) that has been shown to exert cardioprotective effects. In this way, great compilations about Ang-(1-7) actions in the heart have been presented in the literature. However, much less information is available concerning the Ang-(1-7) actions directly in cardiomyocytes. In this paper, we show the actual knowledge about Ang-(1-7)-mediated signaling in cardiac cells more specifically we provide a brief overview of ACE2/Ang-(1-7)/Mas axis; and highlight the discoveries made in cardiomyocyte physiology through the use of genetic approaches. Finally, we discuss the protective signaling induced by Ang-(1-7) in cardiomyocytes and point molecular determinants of these effects.
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Pereira HJV, Souza LL, Costa-Neto CM, Salgado MCO, Oliveira EB. Carboxypeptidases A1 and A2 from the perfusate of rat mesenteric arterial bed differentially process angiotensin peptides. Peptides 2012; 33:67-76. [PMID: 22178042 DOI: 10.1016/j.peptides.2011.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 12/01/2011] [Accepted: 12/01/2011] [Indexed: 01/24/2023]
Abstract
Here we report the isolation of carboxypeptidases A1 and A2 (CPA1 and CPA2) from the rat mesenteric arterial bed perfusate, which were found to be identical with their pancreatic counterparts. Angiotensin (Ang) I, Ang II, Ang-(1-9) and Ang-(1-12) were differentially processed by these enzymes, worthy mentioning the peculiar CPA1-catalyzed conversion of Ang II to Ang-(1-7) and the CPA2-mediated formation of Ang I from Ang-(1-12). We detected gene transcripts for CPA1 and CPA2 in mesentery and other extrapancreatic tissues, indicating that these CPAs might play a role in the renin-angiotensin system in addition to their functions as digestive enzymes.
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Affiliation(s)
- Hugo J V Pereira
- University of São Paulo, Faculty of Medicine of Ribeirão Preto, Department of Biochemistry and Immunology Ribeirão Preto, SP 14049-900, Brazil
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30
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Ahmad S, Simmons T, Varagic J, Moniwa N, Chappell MC, Ferrario CM. Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue. PLoS One 2011; 6:e28501. [PMID: 22180785 PMCID: PMC3236741 DOI: 10.1371/journal.pone.0028501] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Accepted: 11/09/2011] [Indexed: 01/05/2023] Open
Abstract
Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure). PM was incubated with highly purified ¹²⁵I-Ang-(1-12) at 37°C for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase; 50 µM each]. ¹²⁵I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, ¹²⁵I-Ang-(1-12) was converted into Ang I (2±2%), Ang II (69±21%), Ang-(1-7) (5±2%), and Ang-(1-4) (2±1%). In the absence of all RAS inhibitor, only 22±10% of ¹²⁵I-Ang-(1-12) was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of ¹²⁵I-Ang-(1-12) remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that ¹²⁵I-Ang-(1-12) was primarily converted into Ang II (65±18%) by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol × min⁻¹ × mg⁻¹, n = 9) from ¹²⁵I-Ang-(1-12) and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min⁻¹ × mg⁻¹). Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12).
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Affiliation(s)
- Sarfaraz Ahmad
- Division of Surgical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
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31
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Nagata S, Kato J, Kuwasako K, Asami M, Kitamura K. Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system. Hypertens Res 2011; 35:234-8. [PMID: 21993212 DOI: 10.1038/hr.2011.165] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg(-1) per day losartan, an angiotensin receptor blocker, or with 20 mg kg(-1) per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.
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Affiliation(s)
- Sayaka Nagata
- Department of Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
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32
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Mason RP. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. Vasc Health Risk Manag 2011; 7:405-16. [PMID: 21796255 PMCID: PMC3141913 DOI: 10.2147/vhrm.s20737] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Indexed: 12/19/2022] Open
Abstract
Cardiovascular (CV) disease is a major factor in mortality rates around the world and contributes to more than one-third of deaths in the US. The underlying cause of CV disease is atherosclerosis, a chronic inflammatory process that is clinically manifested as coronary artery disease, carotid artery disease, or peripheral artery disease. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Consequently, developing a treatment regimen that can slow or even reverse the atherosclerotic process is imperative. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with CV risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. Since the renin-angiotensin-aldosterone system (RAAS) plays a key role in vascular inflammatory responses, hypertension treatment with RAAS-blocking agents (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers [ARBs]) may slow inflammatory processes and disease progression. Reduced nitric oxide (NO) bioavailability has an important role in the process of endothelial dysfunction and hypertension. Therefore, agents that increase NO and decrease oxidative stress, such as ARBs and ACEIs, may interfere with atherosclerosis. Studies show that angiotensin II type 1 receptor antagonism with an ARB improves endothelial function and reduces atherogenesis. In patients with hypertension, the ARB olmesartan medoxomil provides effective blood pressure lowering, with inflammatory marker studies demonstrating significant RAAS suppression. Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS). Although CV outcomes were not assessed in these studies, the observed benefits in surrogate endpoints of disease suggest that RAAS suppression with olmesartan medoxomil may potentially have beneficial effects on CV outcomes in these patient populations.
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Affiliation(s)
- R Preston Mason
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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33
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Abstract
The assessment of salt sensitivity of blood pressure is difficult because of the lack of universal consensus on definition. Regardless of the variability in the definition of salt sensitivity, increased salt intake, independent of the actual level of blood pressure, is also a risk factor for cardiovascular morbidity and mortality and kidney disease. A modest reduction in salt intake results in an immediate decrease in blood pressure, with long-term beneficial consequences. However, some have suggested that dietary sodium restriction may not be beneficial to everyone. Thus, there is a need to distinguish salt-sensitive from salt-resistant individuals, but it has been difficult to do so with phenotypic studies. Therefore, there is a need to determine the genes that are involved in salt sensitivity. This review focuses on genes associated with salt sensitivity, with emphasis on the variants associated with salt sensitivity in humans that are not due to monogenic causes. Special emphasis is given to gene variants associated with salt sensitivity whose protein products interfere with cell function and increase blood pressure in transgenic mice.
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Affiliation(s)
- Hironobu Sanada
- Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan.
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34
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Shen XZ, Bernstein KE. The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis. Cell Cycle 2011; 10:1363-9. [PMID: 21441775 DOI: 10.4161/cc.10.9.15444] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The concept of a local bone marrow renin-angiotensin system (RAS) has been introduced and accumulating evidence suggests that the local RAS is actively involved in hematopoiesis. Angiotensin converting enzyme (ACE) is a key player in the RAS and makes the final effector angiotensin II. Besides angiotensin II, ACE also regulates a panel of bioactive peptides, such as substance P, Ac-SDKP and angiotensin 1-7. These peptides have also been individually reported in the regulation of pathways of hematopoiesis. In this setting, an ACE-regulated peptide network orchestrating hematopoiesis has emerged. Here, we focus on this peptide network and discuss the roles of ACE and its peptides in aspects of hematopoiesis. Special attention is given to the recent revelation that ACE is a bona fide marker of hematopoietic stem cells.
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Affiliation(s)
- Xiao Z Shen
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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35
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Lu HL, Wang ZY, Huang X, Han YF, Wu YS, Guo X, Kim YC, Xu WX. Excitatory regulation of angiotensin II on gastric motility and its mechanism in guinea pig. ACTA ACUST UNITED AC 2011; 167:170-6. [PMID: 21256873 DOI: 10.1016/j.regpep.2011.01.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 01/11/2011] [Accepted: 01/14/2011] [Indexed: 11/24/2022]
Abstract
In the present study, we investigated the effect of Ang II on gastric smooth muscle motility and its mechanism using intracellular recording and whole-cell patch clamp techniques. Ang II dose-dependently increased the tonic contraction and the frequency of spontaneous contraction in the gastric antral circular smooth muscles of guinea pig. ZD7155, an Ang II type 1 receptor (AT(1)R) blocker, completely blocked the effect of Ang II on the spontaneous contraction of gastric smooth muscle. In contrast, TTX, a sodium channel blocker, failed to block the effect. Furthermore, nicardipine, a voltage-gated Ca(2+)-channel antagonist, did not block the effect of Ang II on the tonic contraction of gastric smooth muscle, but external free-calcium almost completely blocked this effect. Both ryanodine, an inhibitor of calcium-induced Ca(2+) release (CICR) from ryanodine-sensitive calcium stores, and thapsigargin, which depletes calcium in calcium stores, almost completely blocked the effect of Ang II on tonic contraction. However, 2-APB, an inositol trisphosphate (IP(3)) receptor blocker, significantly, but not completely, blocked the Ang II effect on tonic contraction. We also determined that Ang II depolarized membrane potential and increased slow wave frequency in a dose-dependent manner. It also inhibited delayed rectifying potassium currents in a dose-dependent manner, but did not affect L-type calcium currents or calcium-activated potassium currents. These results suggest that Ang II plays an excitatory regulation in gastric motility via AT(1)R-IP(3) and the CICR signaling pathway. The Ang II-induced inhibition of delayed rectifying potassium currents that depolarize membrane potential is also involved in the potentiation of tonic contraction and the frequency of spontaneous contraction in the gastric smooth muscle of guinea pig.
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Affiliation(s)
- Hong-Li Lu
- Department of Physiology, Shanghai Jiaotong University School of Medicine, 800 Dongchuan Road, 328# Wenxuan Medical Building, Shanghai, 200240, China
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36
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Arakawa H, Chitravanshi VC, Sapru HN. The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol 2010; 300:H951-60. [PMID: 21186269 DOI: 10.1152/ajpheart.01144.2010] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The hypothalamic arcuate nucleus (ARCN) has been reported to play a significant role in cardiovascular regulation. It has been hypothesized that the ARCN may be one of the sites of cardiovascular actions of angiotensins (ANGs). Experiments were carried out in urethane-anesthetized, artificially ventilated, adult male Wistar rats. The ARCN was identified by microinjections of N-methyl-d-aspartic acid (NMDA; 10 mM). Microinjections (50 nl) of ANG-(1-12) (1 mM) into the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA). The tachycardic responses to ANG-(1-12) were attenuated by bilateral vagotomy. The cardiovascular responses elicited by ANG-(1-12) were attenuated by microinjections of ANG II type 1 receptor (AT(1)R) antagonists but not ANG type 2 receptor (AT(2)R) antagonist. Combined inhibition of ANG-converting enzyme (ACE) and chymase in the ARCN abolished ANG-(1-12)-induced responses. Microinjections of ANG II (1 mM) into the ARCN also increased MAP and HR. Inhibition of ARCN by microinjections of muscimol (1 mM) attenuated the pressor and tachycardic responses to intravenously administered ANG-(1-12) and ANG II (300 pmol/kg each). These results indicated that 1) microinjections of ANG-(1-12) into the ARCN elicited increases in MAP, HR, and GSNA; 2) HR responses were mediated via both sympathetic and vagus nerves; 3) AT(1)Rs, but not AT(2)Rs, in the ARCN mediated ANG-(1-12)-induced responses; 4) both ACE and chymase were needed to convert ANG-(1-12) to ANG II in the ARCN; and 5) ARCN plays a role in mediating the cardiovascular responses to circulating ANGs.
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Affiliation(s)
- Hideki Arakawa
- Department of Neurological Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA
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37
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Chitravanshi VC, Sapru HN. Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat. Am J Physiol Heart Circ Physiol 2010; 300:H230-40. [PMID: 21076017 DOI: 10.1152/ajpheart.00861.2010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cardiovascular effects of angiotensin-(1-12) [ANG-(1-12)] were studied in the medial nucleus of the tractus solitarius (mNTS) in anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of ANG-(1-12) (0.06 mM) into the mNTS elicited maximum decreases in mean arterial pressure (MAP; 34 ± 5.8 mmHg) and heart rate (HR; 39 ± 3.7 beats/min). Bilateral vagotomy abolished ANG-(1-12)-induced bradycardia. Efferent greater splanchnic nerve activity was decreased by microinjections of ANG-(1-12) into the mNTS. Blockade of ANG type 1 receptors (AT(1)Rs; using ZD-7155 or L-158,809), but not ANG type 2 receptors (AT(2)Rs; using PD-123319), significantly attenuated ANG-(1-12)-induced cardiovascular responses. Simultaneous inhibition of both angiotensin-converting enzyme (ACE; using captopril) and chymase (using chymostatin) completely blocked the effects of ANG-(1-12). Microinjections of A-779 [ANG-(1-7) antagonist] did not attenuate ANG-(1-12)-induced responses. Pressure ejection of ANG-(1-12) (0.06 mM, 2 nl) caused excitation of barosensitive mNTS neurons, which was blocked by prior application of the AT(1)R antagonist. ANG-(1-12)-induced excitation of mNTS neurons was also blocked by prior sequential applications of captopril and chymostatin. These results indicate that 1) microinjections of ANG-(1-12) into the mNTS elicited depressor and bradycardic responses by exciting barosensitive mNTS neurons; 2) the decreases in MAP and HR were mediated via sympathetic and vagus nerves, respectively; 3) AT(1)Rs, but not AT(2)Rs, mediated these actions of ANG-(1-12); 4) the responses were mediated via the conversion of ANG-(1-12) to ANG II and both ACE and chymase were involved in this conversion; and 5) ANG-(1-7) was not one of the metabolites of ANG-(1-12) in the mNTS.
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Affiliation(s)
- Vineet C Chitravanshi
- Department of Neurological Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA
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38
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Robbins ME, Zhao W, Garcia-Espinosa MA, Diz DI. Renin-angiotensin system blockers and modulation of radiation-induced brain injury. Curr Drug Targets 2010; 11:1413-22. [PMID: 20583976 PMCID: PMC3068470 DOI: 10.2174/1389450111009011413] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Accepted: 04/05/2010] [Indexed: 01/05/2023]
Abstract
Radiation-induced brain injury remains a major cause of morbidity in cancer patients with primary or metastatic brain tumors. Approximately 200,000 individuals/year are treated with fractionated partial or whole-brain irradiation, and > half will survive long enough (≤6 months) to develop radiation-induced brain injury, including cognitive impairment. Although short-term treatments have shown efficacy, no long-term treatments or preventive approaches are presently available for modulating radiation-induced brain injury. Based on previous preclinical studies clearly demonstrating that renin-angiotensin system (RAS) blockers can modulate radiation-induced late effects in the kidney and lung, we and others hypothesized that RAS blockade would similarly modulate radiation-induced brain injury. Indeed, studies in the last 5 years have shown that both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor antagonists (AT(1)RAs) can prevent/ameliorate radiation-induced brain injury, including cognitive impairment, in the rat. The mechanistic basis for this RAS blocker-mediated effect remains the subject of ongoing investigations. Putative mechanisms include, i] blockade of Ang II/NADPH oxidase-mediated oxidative stress and neuroinflammation, and ii] a change in the balance of angiotensin (Ang) peptides from the pro-inflammatory and pro-oxidative Ang II to the anti-inflammatory and anti-oxidative Ang-1-7). However, given that both ACEIs and AT(1)RAs are 1] well-tolerated drugs routinely prescribed for hypertension, 2] exhibit some antitumor properties, and 3] can prevent/ameliorate radiation-induced brain injury, they appear to be ideal drugs for future clinical trials, offering the promise of improving the quality of life of brain tumor patients receiving brain irradiation.
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Affiliation(s)
- M E Robbins
- Department of Radiation Oncology, Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
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39
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40
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Savergnini SQ, Beiman M, Lautner RQ, de Paula-Carvalho V, Allahdadi K, Pessoa DC, Costa-Fraga FP, Fraga-Silva RA, Cojocaru G, Cohen Y, Bader M, de Almeida AP, Rotman G, Santos RAS. Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor. Hypertension 2010; 56:112-20. [DOI: 10.1161/hypertensionaha.110.152942] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mas stimulation with angiotensin (Ang)-(1-7) produces cardioprotective effects and vasorelaxation. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate G protein–coupled receptors, we discovered a novel Mas agonist peptide, CGEN-856S. An endothelium- and NO-dependent vasodilating effect was observed for CGEN-856S in thoracic aorta rings of rats (maximal value for the relaxant effect: 39.99±5.034%), which was similar to that produced by Ang-(1-7) (10
−10
to 10
−6
mol/L). In addition, the vasodilator activity of this peptide depended on a functional Mas receptor, because it was abolished in aorta rings of Mas-knockout mice. CGEN-856S appears to bind the Mas receptor at the same binding domain as Ang-(1-7), as suggested by the blocking of its vasorelaxant effect with the Ang-(1-7) analogue
d
-Ala
7
-Ang-(1-7), and by its competitive inhibition of Ang-(1-7) binding to
Mas
-transfected cells. The effect of CGEN-856S on reperfusion arrhythmias and cardiac function was studied on ischemia reperfusion of isolated rat hearts. We found that picomolar concentration of CGEN-856S (0.04 nmol/L) had an antiarrhythmogenic effect, as demonstrated by a reduction in the incidence and duration of reperfusion arrhythmias. Furthermore, acute infusion of CGEN-856S produced a shallow dose-dependent decrease in mean arterial pressure of conscious spontaneously hypertensive rats. The maximum change during infusion was observed at the highest dose. Strikingly, blood pressure continued to drop in the postinfusion period. The results presented here indicate that the novel Mas agonist, CGEN-856S, might have a therapeutic value, because it induces vasorelaxing, antihypertensive, and cardioprotective effects.
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Affiliation(s)
- Silvia Quintão Savergnini
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Merav Beiman
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Roberto Queiroga Lautner
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Vanice de Paula-Carvalho
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Kyan Allahdadi
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Dalton Caires Pessoa
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Fabiana Pereira Costa-Fraga
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Rodrigo Araújo Fraga-Silva
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Gady Cojocaru
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Yossi Cohen
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Michael Bader
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Alvair Pinto de Almeida
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Galit Rotman
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
| | - Robson Augusto Souza Santos
- From the Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar) (S.Q.S., R.Q.L., V.P.-C., K.A., D.C.P., F.P.C.-F., R.A.F.-S., A.P.A., R.A.S.S.), Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Compugen Ltd (M.Be., G.C., Y.C., G.R.), Tel Aviv, Israel; Max-Delbrück-Center for Molecular Medicine (M.Ba.), Berlin-Buch, Germany
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High sucrose intake in rats is associated with increased ACE2 and angiotensin-(1–7) levels in the adipose tissue. ACTA ACUST UNITED AC 2010; 162:61-7. [DOI: 10.1016/j.regpep.2010.03.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2009] [Revised: 01/28/2010] [Accepted: 03/16/2010] [Indexed: 11/19/2022]
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Nagata S, Kato J, Kuwasako K, Kitamura K. Plasma and tissue levels of proangiotensin-12 and components of the renin-angiotensin system (RAS) following low- or high-salt feeding in rats. Peptides 2010; 31:889-92. [PMID: 20172005 DOI: 10.1016/j.peptides.2010.02.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Revised: 02/10/2010] [Accepted: 02/10/2010] [Indexed: 01/13/2023]
Abstract
The renin-angiotensin system (RAS) is an essential regulator of the blood pressure and body fluid balance, but the processing cascade or role of the tissue RAS remains obscure. Proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, is assumed to function as a factor of the tissue RAS. To investigate the tissue production of proang-12, we measured the circulating and tissue components of the RAS including proang-12 following low-, normal-, or high-salt feeding in rats. Twelve-week-old male Wistar rats were fed a low-salt 0.3% NaCl or high-salt 8% NaCl diet for 7 days and compared with those fed a normal-salt diet of 0.7% NaCl. Low-salt feeding elevated the plasma renin activity and aldosterone concentration, resulting in significant increases in Ang I and Ang II levels in the plasma or kidney tissue, as compared with the normal- or high-salt group. Despite the increases in plasma renin activity, Ang I, and Ang II, the proang-12 levels in plasma and various tissues including the kidneys, small intestine, cardiac ventricles, and brain remained unchanged following low-salt feeding. These results suggest that peptide levels of proang-12 in rat plasma and tissues are regulated in a manner independent of the circulating RAS.
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Affiliation(s)
- Sayaka Nagata
- Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
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Castrop H, Höcherl K, Kurtz A, Schweda F, Todorov V, Wagner C. Physiology of Kidney Renin. Physiol Rev 2010; 90:607-73. [PMID: 20393195 DOI: 10.1152/physrev.00011.2009] [Citation(s) in RCA: 199] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).
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Affiliation(s)
- Hayo Castrop
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Klaus Höcherl
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Armin Kurtz
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Frank Schweda
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Vladimir Todorov
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Charlotte Wagner
- Institute of Physiology, University of Regensburg, Regensburg, Germany
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Abstract
Although initially considered relatively harmless pathogens, human coronaviruses (HCoVs) are nowadays known to be associated with more severe clinical complications. Still, their precise pathogenic potential is largely unknown, particularly regarding the most recently identified species HCoV-NL63 and HCoV-HKU1. HCoVs need host cell proteins to successively establish infections. Proteases of the renin–angiotensin system serve as receptors needed for entry into target cells; this article describes the current knowledge on the involvement of this system in HCoV pathogenesis.
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Affiliation(s)
- Brigitte A Wevers
- Center for Experimental & Molecular Medicine, Center for Infection & Immunity Amsterdam, Academic Medical Center, University of Amsterdam, PO Box 226600, 1100 DD Amsterdam, The Netherlands.
| | - Lia van der Hoek
- Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection & Immunity Amsterdam, Academic Medical Center, University of Amsterdam, PO Box 226600, 1100 DD Amsterdam, The Netherlands. Tel.: +31 205 667 510; ;
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Zhou LM, Shi Z, Gao J, Han Y, Yuan N, Gao XY, Zhu GQ. Angiotensin-(1–7) and angiotension II in the rostral ventrolateral medulla modulate the cardiac sympathetic afferent reflex and sympathetic activity in rats. Pflugers Arch 2010; 459:681-8. [DOI: 10.1007/s00424-010-0793-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Revised: 01/25/2010] [Accepted: 01/27/2010] [Indexed: 12/19/2022]
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Impairment of the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas axis contributes to the acceleration of two-kidney, one-clip Goldblatt hypertension. J Hypertens 2010; 27:1988-2000. [PMID: 19593210 DOI: 10.1097/hjh.0b013e32832f0d06] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Recent studies have shown that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] exerts important vasoactive actions and can act as an endogenous physiological antagonist of angiotensin II (Ang II) within the renin-angiotensin system (RAS). The present study was performed to evaluate the effects, first, of chronic increases of Ang-(1-7) levels, second, of [7-D-Ala], an Ang-(1-7) receptor antagonist, and, third, of an angiotensin-converting enzyme 2 (ACE2) inhibitor on the course of hypertension and of renal function of the nonclipped kidney in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats. METHODS Blood pressure (BP) was monitored by radiotelemetry. Elevation of the effect of circulating Ang-(1-7) levels was achieved either by chronic subcutaneous infusion of Ang-(1-7) through osmotic minipumps or by employing transgenic rats that express an Ang-(1-7)-producing fusion protein [Ang-(1-7)TGR+/+] (and its control Ang-(1-7)TGR-/-). [7-D-Ala] was also infused subcutaneously and the ACE2 inhibitor was administrated in drinking water. On day 25 after clipping, rats were anesthetized and renal function was evaluated. RESULTS Chronic infusion of Ang-(1-7) did not modify the course of 2K1C hypertension and did not alter renal function as compared with saline vehicle-infused 2K1C rats. Chronic infusion of [7-D-Ala] or treatment with the ACE2 inhibitor worsened the course of hypertension and elicited decreases in renal hemodynamics. [Ang-(1-7)TGR+/+] and [Ang-(1-7)TGR-/-] rats exhibited a similar course of hypertension. CONCLUSION The present data support the notion that Ang-(1-7) serves as an important endogenous vasodilator and natriuretic agent and its deficiency might contribute to the acceleration of 2K1C Goldblatt hypertension.
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van der Harst P, de Boer RA, Samani NJ, Wong LSM, Huzen J, Codd V, Hillege HL, Voors AA, van Gilst WH, Jaarsma T, van Veldhuisen DJ. Telomere length and outcome in heart failure. Ann Med 2010; 42:36-44. [PMID: 19941413 DOI: 10.3109/07853890903321567] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Telomeres are causally involved in senescence. Senescence is a potential factor in the pathogenesis and progression of heart failure. In heart failure telomeres are shorter, but the prognostic value associated with telomere length has not been defined. METHODS Telomere length was prospectively determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association (NYHA) functional class II to IV heart failure. After 18 months, we examined the association between telomere length and the predefined primary end-point: time to death or hospitalization for heart failure. RESULTS Mean age of the patients was 71 years, 39% were women, 51% were in NYHA class II, and 49% were in class III/IV. A total of 344 patients reached the primary end-point (130 deaths and 214 hospitalizations). Patients with shorter telomeres were at an increased risk of reaching the primary end-point (hazard ratio 1.79; 95% confidence interval (CI) 1.21-2.63). In multivariate analysis shorter telomere length remained associated with a higher risk for death or hospitalization (hazard ratio, 1.74; 95% CI 1.07-2.95) after adjustment for age of heart failure onset, gender, hemoglobin, renal function, and N-terminal pro-B-type natriuretic peptide level, a history of stroke, atrial fibrillation, and diabetes. CONCLUSIONS Shorter length of telomeres predicts the occurrence of death or hospitalization in patients with chronic heart failure.
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Affiliation(s)
- Pim van der Harst
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
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Comparison of the long-term effects of candesartan and olmesartan on plasma angiotensin II and left ventricular mass index in patients with hypertension. Hypertens Res 2009; 33:118-22. [PMID: 19927151 DOI: 10.1038/hr.2009.192] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In general, treatment with most angiotensin receptor blockers (ARBs) increases plasma angiotensin II (Ang II) level because of a lack of negative feedback on renin activity. Olmesartan is a potential ARB inducing activation of angiotensin-converting enzyme 2 (ACE2) that hydrolyzes Ang II to Ang 1-7, and has shown a beneficial effect on ventricular remodeling. Indeed, a previous study reported that olmesartan treatment resulted in decreased plasma levels of Ang II and aldosterone. However, there has not yet been a study showing the relationship of chronic effects of olmesartan on Ang II and the left ventricular mass index (LVMI) in comparison with those of other ARB.A total of 50 stable outpatients with essential hypertension who had received candesartan for more than 1 year were randomized into two groups: control group (n=25): continuous candesartan treatment at a stable dose; and olmesartan group (n=25): candesartan (8 mg day(-1)) was changed to olmesartan given at a dose of 20 mg day(-1). There was no difference in the baseline characteristics between the two groups. In the control group, there were no significant changes in blood pressure, LVMI or biomarkers during 12 months of study. In the olmesartan group, blood pressure did not change and plasma levels of Ang II decreased during 12 months of study, whereas LVMI was significantly decreased after 12 months (135+/-36 vs. 123+/-29 g m(-2); P<0.01).These findings indicate that replacing candesartan with olmesartan decreased LVMI in association with a sustained decrease of plasma Ang II over a 12-month period without changing blood pressure or plasma aldosterone in patients with essential hypertension.
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Jain G, Campbell RC, Warnock DG. Mineralocorticoid receptor blockers and chronic kidney disease. Clin J Am Soc Nephrol 2009; 4:1685-91. [PMID: 19729430 DOI: 10.2215/cjn.01340209] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The increasing prevalence of chronic kidney disease (CKD) and the public health initiatives for detection and slowing its progression have placed special emphasis on controlling proteinuria and the renin-angiotensin-aldosterone system (RAAS). In addition to the traditional blockers of angiotensin-converting enzyme and angiotensin receptors, mineralocorticoid receptor blockers (MRBs) have come into focus as anti-proteinuric agents with moderate anti-hypertensive effects. The beneficial effects of MRBs on mortality in patients with cardiac disease have been well described. We review the role of aldosterone in end-organ damage, the rationales for using MRBs as adjuncts to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in treating CKD, and the adverse effects that may occur when these agents are used in combination. Suggestions are included for avoiding serious adverse events in CKD patients treated with MRBs. There is a clearly defined need for prospective outcome studies focused on cardiovascular mortality as well as progression of CKD in patients treated with MRBS and other inhibitors of the RAAS.
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Affiliation(s)
- Gaurav Jain
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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10th Annual Congress of the German Association of Clinical Pharmacology. Basic Clin Pharmacol Toxicol 2009; 104:491-528. [DOI: 10.1111/j.1742-7843.2009.00424.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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