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Biomedicines
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Renin-Angiotensin System in Cardiovascular Biology
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Renin-Angiotensin System in Cardiovascular Biology

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 9393

Special Issue Editors

Dr. Mária Szekeres

E-Mail Website
Guest Editor
Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 1088 Budapest, Hungary
Interests: renin-angiotensin system (RAS); vascular; hypertension; atherosclerosis; endocannabinoid
Dr. György L. Nádasy

E-Mail Website
Guest Editor
Department of Physiology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary
Interests: cardiovascular physiology; angiotensin II; renin-angiotensin system (RAS); vascular; hypertension
Dr. András Balla

E-Mail Website
Guest Editor
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094 Budapest, Hungary
Interests: physiology; signal transduction; G-protein-coupled receptors (GPCRs); angiotensin II; renin-angiotensin system (RAS)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to present the latest updates on the role of the renin-angiotensin system (RAS) in cardiovascular biology, from cellular mechanisms to organ functions and novel therapeutic mechanisms. The RAS has an important role in the regulation of blood pressure and salt water homeostasis. Angiotensin II (AngII) is the main regulator, which operates by stimulating AT1 receptors, a member of G protein-coupled receptor family, and activating mainly calcium signaling mechanisms inducing, e.g., smooth muscle contraction, vasoconstriction and blood pressure elevation. Long-term overactivation of the RAS may result in inflammatory mechanisms, vascular hypertrophy and remodeling, water retention, hypertension and atherosclerosis. Therapies based on angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and blockers of AT1 angiotensin receptors have been effectively used in the therapy of hypertension for decades. Other RAS pathways have more recently become the focus of research, including ACE2 and AT2 receptor signaling, as well as the conversion of AngII to Ang 1-7, which may provide links between the deleterious and beneficial actions of RAS. Alternative activation of these pathways may also propose novel additional molecular mechanisms and beneficial therapeutic potential in cardiovascular pathology.

This Special Issue therefore invites original research papers and review articles providing the latest insights into the complexity of the cell signaling and biological mechanisms of the RAS components to propose novel mechanisms in cardiovascular physiology and pathophysiology. By targeting this system, works may provide novel therapeutic potential in cardiovascular and related diseases such as hypertension, heart failure, atherosclerosis and diabetes mellitus.

Dr. Mária Szekeres
Dr. György L. Nádasy
Dr. András Balla
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • renin-angiotensin system (RAS)
  • signaling mechanisms of angiotensin receptors
  • GPCR
  • AT1R
  • AT2R
  • ACE
  • ACE2
  • ACEI
  • angiotensin II
  • signal transduction
  • cardiovascular system
  • hypertension
  • atherosclerosis
  • heart failure

Published Papers (7 papers)

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Editorial

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9 pages, 268 KiB  
Editorial
From Living in Saltwater to a Scarcity of Salt and Water, and Then an Overabundance of Salt—The Biological Roller Coaster to Which the Renin–Angiotensin System Has Had to Adapt: An Editorial
by György L. Nádasy, András Balla and Mária Szekeres
Biomedicines 2023, 11(11), 3004; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11113004 - 09 Nov 2023
Cited by 1 | Viewed by 755
Abstract
Angiotensin II (Ang II) is a hormone with much more complex actions than is typical for other agonists with heterotrimeric G protein-coupled receptors (GPCRs) [...] Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)

Research

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10 pages, 1147 KiB  
Article
Classical and Alternative Pathways of the Renin–Angiotensin–Aldosterone System in Regulating Blood Pressure in Hypertension and Obese Adolescents
by Adrian Martyniak, Dorota Drożdż and Przemysław J. Tomasik
Biomedicines 2024, 12(3), 620; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030620 - 10 Mar 2024
Viewed by 675
Abstract
Primary hypertension (PH) is the leading form of arterial hypertension (AH) in adolescents. Hypertension is most common in obese patients, where 20 to 40% of the population has elevated blood pressure. One of the most effective mechanisms for regulating blood pressure is the [...] Read more.
Primary hypertension (PH) is the leading form of arterial hypertension (AH) in adolescents. Hypertension is most common in obese patients, where 20 to 40% of the population has elevated blood pressure. One of the most effective mechanisms for regulating blood pressure is the renin–angiotensin–aldosterone system (RAAS). The new approach to the RAAS talks about two opposing pathways between which a state of equilibrium develops. One of them is a classical pathway, which is responsible for increasing blood pressure and is represented mainly by the angiotensin II (Ang II) peptide and, to a lesser extent, by angiotensin IV (Ang IV). The alternative pathway is responsible for the decrease in blood pressure and is mainly represented by angiotensin 1–7 (Ang 1–7) and angiotensin 1–9 (Ang 1–9). Our research study aimed to assess changes in angiotensin II, angiotensin IV, angiotensin 1–7, and angiotensin 1–9 concentrations in the plasma of adolescents with hypertension, with hypertension and obesity, and obesity patients. The Ang IV concentration was lower in hypertension + obesity versus control and obesity versus control, respectively p = 0.01 and p = 0.028. The Ang 1–9 concentration was lower in the obesity group compared to the control group (p = 0.036). There were no differences in Ang II and Ang 1–7 peptide concentrations in the hypertension, hypertension and obesity, obesity, and control groups. However, differences were observed in the secondary peptides, Ang IV and Ang 1–9. In both cases, the differences were related to obesity. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)
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13 pages, 1276 KiB  
Article
Enalapril Is Superior to Lisinopril in Improving Endothelial Function without a Difference in Blood–Pressure–Lowering Effects in Newly Diagnosed Hypertensives
by Attila Nagy, Réka Májer, Judit Boczán, Sándor Sipka, Jr., Attila Szabó, Enikő Edit Enyedi, Ottó Tatai, Miklós Fagyas, Zoltán Papp, László Csiba and Attila Tóth
Biomedicines 2023, 11(12), 3323; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11123323 - 15 Dec 2023
Cited by 1 | Viewed by 1088
Abstract
Angiotensin–converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. Goal: Here, we tested if lipophilicity affects [...] Read more.
Angiotensin–converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. Goal: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. Methods: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. Results: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood–pressure–lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. Conclusion: The blood–pressure–lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)
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17 pages, 1151 KiB  
Article
Association of Elevated Serum Aldosterone Concentrations in Pregnancy with Hypertension
by Robin Shoemaker, Marko Poglitsch, Dolph Davis, Hong Huang, Aric Schadler, Neil Patel, Katherine Vignes, Aarthi Srinivasan, Cynthia Cockerham, John A. Bauer and John M. O’Brien
Biomedicines 2023, 11(11), 2954; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11112954 - 01 Nov 2023
Viewed by 1329
Abstract
Emerging evidence indicates a previously unrecognized, clinically relevant spectrum of abnormal aldosterone secretion associated with hypertension severity. It is not known whether excess aldosterone secretion contributes to hypertension during pregnancy. We quantified aldosterone concentrations and angiotensin peptides in serum (using liquid chromatography with [...] Read more.
Emerging evidence indicates a previously unrecognized, clinically relevant spectrum of abnormal aldosterone secretion associated with hypertension severity. It is not known whether excess aldosterone secretion contributes to hypertension during pregnancy. We quantified aldosterone concentrations and angiotensin peptides in serum (using liquid chromatography with tandem mass spectrometry) in a cohort of 128 pregnant women recruited from a high-risk obstetrics clinic and followed prospectively for the development of gestational hypertension, pre-eclampsia, superimposed pre-eclampsia, chronic hypertension, or remaining normotensive. The cohort was grouped by quartile of aldosterone concentration in serum measured in the first trimester, and blood pressure, angiotensin peptides, and hypertension outcomes compared across the four quartiles. Blood pressures and body mass index were greatest in the top and bottom quartiles, with the top quartile having the highest blood pressure throughout pregnancy. Further stratification of the top quartile based on increasing (13 patients) or decreasing (19 patients) renin activity over gestation revealed that the latter group was characterized by the highest prevalence of chronic hypertension, use of anti-hypertensive agents, pre-term birth, and intrauterine growth restriction. Serum aldosterone concentrations greater than 704 pmol/L, the 75th percentile defined within the cohort, were evident across all categories of hypertension in pregnancy, including normotensive. These findings suggest that aldosterone excess may underlie the development of hypertension in pregnancy in a significant subpopulation of individuals. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)
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17 pages, 2197 KiB  
Article
Physical Training vs. Perindopril Treatment on Arterial Stiffening of Spontaneously Hypertensive Rats: A Proteomic Analysis and Possible Mechanisms
by Danyelle Siqueira Miotto, Francine Duchatsch, Aline Dionizio, Marília Afonso Rabelo Buzalaf and Sandra Lia Amaral
Biomedicines 2023, 11(5), 1381; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11051381 - 06 May 2023
Cited by 1 | Viewed by 1288
Abstract
(1) Background: Arterial stiffness is an important predictor of cardiovascular events. Perindopril and physical exercise are important in controlling hypertension and arterial stiffness, but the mechanisms are unclear. (2) Methods: Thirty-two spontaneously hypertensive rats (SHR) were evaluated for eight weeks: SHRC (sedentary); [...] Read more.
(1) Background: Arterial stiffness is an important predictor of cardiovascular events. Perindopril and physical exercise are important in controlling hypertension and arterial stiffness, but the mechanisms are unclear. (2) Methods: Thirty-two spontaneously hypertensive rats (SHR) were evaluated for eight weeks: SHRC (sedentary); SHRP (sedentary treated with perindopril—3 mg/kg) and SHRT (trained). Pulse wave velocity (PWV) analysis was performed, and the aorta was collected for proteomic analysis. (3) Results: Both treatments determined a similar reduction in PWV (−33% for SHRP and −23% for SHRT) vs. SHRC, as well as in BP. Among the altered proteins, the proteomic analysis identified an upregulation of the EH domain-containing 2 (EHD2) protein in the SHRP group, required for nitric oxide-dependent vessel relaxation. The SHRT group showed downregulation of collagen-1 (COL1). Accordingly, SHRP showed an increase (+69%) in the e-NOS protein level and SHRT showed a lower COL1 protein level (−46%) compared with SHRC. (4) Conclusions: Both perindopril and aerobic training reduced arterial stiffness in SHR; however, the results suggest that the mechanisms can be distinct. While treatment with perindopril increased EHD2, a protein involved in vessel relaxation, aerobic training decreased COL1 protein level, an important protein of the extracellular matrix (ECM) that normally enhances vessel rigidity. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)
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23 pages, 3354 KiB  
Article
Blood ACE Phenotyping for Personalized Medicine: Revelation of Patients with Conformationally Altered ACE
by Sergei M. Danilov, Mark S. Jain, Pavel A. Petukhov, Olga V. Kurilova, Valery V. Ilinsky, Pavel E. Trakhtman, Elena L. Dadali, Larisa M. Samokhodskaya, Armais A. Kamalov and Olga A. Kost
Biomedicines 2023, 11(2), 534; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11020534 - 13 Feb 2023
Cited by 1 | Viewed by 1479
Abstract
Background: The angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated blood ACE is a marker for granulomatous diseases and elevated ACE expression in tissues is associated with increased risk of cardiovascular diseases. [...] Read more.
Background: The angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated blood ACE is a marker for granulomatous diseases and elevated ACE expression in tissues is associated with increased risk of cardiovascular diseases. Objective and Methodology: We applied a novel approach —ACE phenotyping—to find a reason for conformationally impaired ACE in the blood of one particular donor. Similar conformationally altered ACEs were detected previously in 2–4% of the healthy population and in up to 20% of patients with uremia, and were characterized by significant increase in the rate of angiotensin I hydrolysis. Principal findings: This donor has (1) significantly increased level of endogenous ACE inhibitor in plasma with MW less than 1000; (2) increased activity toward angiotensin I; (3) M71V mutation in ABCG2 (membrane transporter for more than 200 compounds, including bilirubin). We hypothesize that this patient may also have the decreased level of free bilirubin in plasma, which normally binds to the N domain of ACE. Analysis of the local conformation of ACE in plasma of patients with Gilbert and Crigler-Najjar syndromes allowed us to speculate that binding of mAbs 1G12 and 6A12 to plasma ACE could be a natural sensor for estimation of free bilirubin level in plasma. Totally, 235 human plasma/sera samples were screened for conformational changes in soluble ACE. Conclusions/Significance: ACE phenotyping of plasma samples allows us to identify individuals with conformationally altered ACE. This type of screening has clinical significance because this conformationally altered ACE could not only result in the enhancement of the level of angiotensin II but could also serve as an indicator of free bilirubin levels. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)
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Review

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15 pages, 1185 KiB  
Review
Role of the Renin-Angiotensin System in Long COVID’s Cardiovascular Injuries
by Elena Cojocaru, Cristian Cojocaru, Cristiana-Elena Vlad and Lucian Eva
Biomedicines 2023, 11(7), 2004; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11072004 - 15 Jul 2023
Cited by 4 | Viewed by 1669
Abstract
The renin-angiotensin system (RAS) is one of the biggest challenges of cardiovascular medicine. The significance of the RAS in the chronic progression of SARS-CoV-2 infection and its consequences is one of the topics that are currently being mostly discussed. SARS-CoV-2 undermines the balance [...] Read more.
The renin-angiotensin system (RAS) is one of the biggest challenges of cardiovascular medicine. The significance of the RAS in the chronic progression of SARS-CoV-2 infection and its consequences is one of the topics that are currently being mostly discussed. SARS-CoV-2 undermines the balance between beneficial and harmful RAS pathways. The level of soluble ACE2 and membrane-bound ACE2 are both upregulated by the endocytosis of the SARS-CoV-2/ACE2 complex and the tumor necrosis factor (TNF)-α-converting enzyme (ADAM17)-induced cleavage. Through the link between RAS and the processes of proliferation, the processes of fibrous remodelling of the myocardium are initiated from the acute phase of the disease, continuing into the long COVID stage. In the long term, RAS dysfunction may cause an impairment of its beneficial effects leading to thromboembolic processes and a reduction in perfusion of target organs. The main aspects of ACE2—a key pathogenic role in COVID-19 as well as the mechanisms of RAS involvement in COVID cardiovascular injuries are studied. Therapeutic directions that can be currently anticipated in relation to the various pathogenic pathways of progression of cardiovascular damage in patients with longCOVID have also been outlined. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review. 

Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardio-Renal Disease
Authors: Shah M and Abdel-Rahman EM
 

Direct and indirect vascular effects of angiotensin II. A Short Review.

 Authors: Nadasy GL, Balla A, Dornyei G, Hunyady L and Szekeres M

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