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Renin-Angiotensin System in Cardiovascular Biology

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

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 20417

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Dr. Mária Szekeres

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

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Department of Physiology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary
Interests: cardiovascular physiology; angiotensin II; renin-angiotensin system (RAS); vascular; hypertension; coronary vessels; cerebral vessels
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Dr. András Balla

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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

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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

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Related Special Issue

Renin-Angiotensin System in Cardiovascular Biology, 2nd Edition in Biomedicines

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

9 pages, 268 KiB

Open AccessEditorial

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://doi.org/10.3390/biomedicines11113004 - 9 Nov 2023

Cited by 1 | Viewed by 1085

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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15 pages, 3926 KiB

Open AccessArticle

Cardiovascular and Renal Effects Induced by Alpha-Lipoic Acid Treatment in Two-Kidney-One-Clip Hypertensive Rats

by Déborah Victória Gomes Nascimento, Darlyson Ferreira Alencar, Matheus Vinicius Barbosa da Silva, Danilo Galvão Rocha, Camila Ferreira Roncari, Roberta Jeane Bezerra Jorge, Renata de Sousa Alves, Richard Boarato David, Wylla Tatiana Ferreira e Silva, Lígia Cristina Monteiro Galindo and Thyago Moreira de Queiroz

Biomedicines 2024, 12(8), 1751; https://doi.org/10.3390/biomedicines12081751 - 3 Aug 2024

Viewed by 1005

Abstract

α-Lipoic acid (LA) is an antioxidant of endogenous production, also obtained exogenously. Oxidative stress is closely associated with hypertension, which causes kidney injury and endothelial dysfunction. Here, we evaluated the cardiovascular and renal effects of LA in the two-kidney-one-clip (2K1C) hypertension model. The rats were divided into four groups: Sham surgery (Sham), the two-kidneys-one-clip (2K1C) group, and groups treated with LA for 14 days (Sham-LA and 2K1C-LA). No changes were observed in the pattern of food, water intake, and urinary volume. The left/right kidney weight LKw/RKw ratio was significantly higher in 2K1C animals. LA treatment did not reverse the increase in cardiac mass. In relation to vascular reactivity, there was an increase in the potency of phenylephrine (PHE) curve in the hypertensive animals treated with LA compared to the 2K1C group and also compared to the Sham group. Vasorelaxation induced by acetylcholine (Ach) and sodium nitroprusside (SNP) were not improved by treatment with LA. Urea and creatinine levels were not altered by the LA treatment. In conclusion, the morphological changes in the aorta and heart were not reversed; however, the treatment with LA mitigated the contraction increase induced by the 2K1C hypertension. Full article

(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)

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11 pages, 2138 KiB

Open AccessArticle

Dabsylated Bradykinin Is Cleaved by Snake Venom Proteases from Echis ocellatus

by Julius Abiola, Anna Maria Berg, Olapeju Aiyelaagbe, Akindele Adeyi and Simone König

Biomedicines 2024, 12(5), 1027; https://doi.org/10.3390/biomedicines12051027 - 7 May 2024

Viewed by 1126

Abstract

The vasoactive peptide bradykinin (BK) is an important member of the renin–angiotensin system. Its discovery is tightly interwoven with snake venom research, because it was first detected in plasma following the addition of viper venom. While the fact that venoms liberate BK from a serum globulin fraction is well described, its destruction by the venom has largely gone unnoticed. Here, BK was found to be cleaved by snake venom metalloproteinases in the venom of Echis ocellatus, one of the deadliest snakes, which degraded its dabsylated form (DBK) in a few minutes after Pro7 (RPPGFSP↓FR). This is a common cleavage site for several mammalian proteases such as ACE, but is not typical for matrix metalloproteinases. Residual protease activity < 5% after addition of EDTA indicated that DBK is also cleaved by serine proteases to a minor extent. Mass spectrometry-based protein analysis provided spectral proof for several peptides of zinc metalloproteinase-disintegrin-like Eoc1, disintegrin EO4A, and three serine proteases in the venom. Full article

(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)

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10 pages, 1147 KiB

Open AccessArticle

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://doi.org/10.3390/biomedicines12030620 - 10 Mar 2024

Cited by 1 | Viewed by 1837

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 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

Open AccessArticle

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://doi.org/10.3390/biomedicines11123323 - 15 Dec 2023

Cited by 1 | Viewed by 4666

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 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

Open AccessArticle

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://doi.org/10.3390/biomedicines11112954 - 1 Nov 2023

Cited by 2 | Viewed by 1922

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 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

Open AccessArticle

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://doi.org/10.3390/biomedicines11051381 - 6 May 2023

Cited by 2 | Viewed by 1764

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: SHR_C (sedentary); SHR_P (sedentary treated with perindopril—3 mg/kg) and SHR_T (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 SHR_P and −23% for SHR_T) vs. SHR_C, 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 SHR_P group, required for nitric oxide-dependent vessel relaxation. The SHR_T group showed downregulation of collagen-1 (COL1). Accordingly, SHR_P showed an increase (+69%) in the e-NOS protein level and SHR_T showed a lower COL1 protein level (−46%) compared with SHR_C. (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

Open AccessArticle

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://doi.org/10.3390/biomedicines11020534 - 13 Feb 2023

Cited by 4 | Viewed by 1964

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. 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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12 pages, 1630 KiB

Open AccessReview

Updates on the Renin–Angiotensin–Aldosterone System and the Cardiovascular Continuum

by Dana Pop, Alexandra Dădârlat-Pop, Raluca Tomoaia, Dumitru Zdrenghea and Bogdan Caloian

Biomedicines 2024, 12(7), 1582; https://doi.org/10.3390/biomedicines12071582 - 17 Jul 2024

Viewed by 1203

Abstract

The cardiovascular continuum describes how several cardiovascular risk factors contribute to the development of atherothrombosis, ischemic heart disease, and peripheral arteriopathy, leading to cardiac and renal failure and ultimately death. Due to its multiple valences, the renin–angiotensin–aldosterone system plays an important role in all stages of the cardiovascular continuum, starting from a cluster of cardiovascular risk factors, and continuing with the development of atherosclerosis thorough various mechanisms, and culminating with heart failure. Therefore, this article aims to analyze how certain components of the renin–angiotensin–aldosterone system (converting enzymes, angiotensin, angiotensin receptors, and aldosterone) are involved in the underlying pathophysiology of the cardiovascular continuum and the possible arrest of its progression. Full article

(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology)

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15 pages, 1185 KiB

Open AccessReview

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://doi.org/10.3390/biomedicines11072004 - 15 Jul 2023

Cited by 6 | Viewed by 2273

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 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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