angiotensin-i and alamandine

Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor-as such, an individual's susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Humans; Oligopeptides; Peptide Fragments; Renin-Angiotensin System

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1-7) [ANG-(1-7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Congresses as Topic; Humans; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction

Renin angiotensin system (RAS) is an endogenous hormone system involved in the control of blood pressure and fluid volume. Dysregulation of RAS has a pathological role in causing cardiovascular diseases through hypertension. Among several key components of RAS, angiotensin peptides, varying in amino acid length and biological function, have important roles in preventing or promoting hypertension, cardiovascular diseases, stroke, vascular remodeling etc. These peptides are generated by the metabolism of inactive angiotensinogen or its derived peptides by hydrolyzing action of certain enzymes. Angiotensin II, angiotensin (1-12), angiotensin A and angiotensin III bind primarily to angiotensin II type 1 receptor and cause vasoconstriction, accumulation of inflammatory markers to sub-endothelial region of blood vessels and activate smooth muscle cell proliferation. Moreover, when bound to angiotensin II type 2 receptor, angiotensin II works as cardio-protective peptide and halt pathological cell signals. Other peptides like angiotensin (1-9), angiotensin (1-7), alamandine and angiotensin IV also help in protecting from cardiovascular diseases by binding to their respective receptors.

Topics: Angiotensin I; Angiotensin II; Angiotensin III; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Humans; Hypertension; Oligopeptides; Peptide Fragments; Protective Factors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction; Vasoconstriction

The purpose of this review was to summarize the current knowledge on the role of angiotensin-(1-7) [Ang-(1-7)] and alamandine in experimental hypertension and atherosclerosis.. The renin-angiotensin system (RAS) is a very complex system, composed of a cascade of enzymes, peptides, and receptors, known to be involved in the pathogenesis of hypertension and atherosclerosis. Ang-(1-7), identified and characterized in 1987, and alamandine, discovered 16 years after, are the newest two main effector molecules from the RAS, protecting the vascular system against hypertension and atherosclerosis. While the beneficial effects of Ang-(1-7) have been widely studied in several experimental models of hypertension, much less studies were performed in experimental models of atherosclerosis. Alamandine has shown similar vascular effects to Ang-(1-7), namely, endothelial-dependent vasorelaxation mediated by nitric oxide and hypotensive effects in experimental hypertension. There are few studies on the effects of alamandine on atherosclerosis.

Topics: Angiotensin I; Animals; Atherosclerosis; Humans; Hypertension; Models, Theoretical; Oligopeptides; Peptide Fragments; Renin-Angiotensin System; Vasodilation

The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Heart Diseases; Humans; Kidney Diseases; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled

A primary peptide of the renin angiotensin system (RAS), Angiotensin (Ang) II, is a vasoconstrictor and promotor of atherosclerosis. To counter this, the RAS also consists of peptides and receptors which increase nitric oxide release from the endothelium and decrease nicotinamide adenine dinucleotide phosphate oxidase-related superoxide production. Two peptides, Ang (1-7) and alamandine are vasodilators, by activating the nitric oxide pathway via different receptors in the endothelium. Thus, herein we focus on the similarities and differences between alamandine and Ang (1-7) and the counterbalancing hypothesis on Ang II during endothelial dysfunction and atherosclerosis.

Topics: Angiotensin I; Animals; Atherosclerosis; Endothelium, Vascular; Humans; Nitric Oxide; Oligopeptides; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Vasodilation; Vasodilator Agents

The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Kidney Diseases; Mice; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Rats; Renin-Angiotensin System

In this article, we review the recent findings regarding a new derivative of angiotensin-(1-7) [Ang-(1-7)], alamandine, and its receptor, the Mas-related G-coupled receptor type D (MrgD) with a special emphasis on its role and how it can be formed.. Over the last decade, there have been significant conceptual changes regarding the understanding of the renin-angiotensin system (RAS). A cardioprotective axis has been elucidated by the discovery of the Mas receptor for the biologically active Ang-(1-7), and the angiotensin-converting enzyme 2 (ACE2) that coverts Ang II into Ang-(1-7). In addition, several components of the system, such as Ang-(1-12), Angiotensin A (Ang A) and the newly discovered peptide, alamandine, have been identified. Alamandine is generated by catalysis of Ang A via ACE2 or directly from Ang-(1-7).. Alamandine is a vasoactive peptide with similar protective actions as Ang-(1-7) that acts through the MrgD and may represent another important counter-regulatory mechanism within the RAS.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensins; Animals; Humans; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction

The renin-angiotensin system is an important component of the central and humoral mechanisms of blood pressure and hydro-electrolytic balance control. Angiotensin II is a key player of this system. Twenty-five years ago the first manuscripts describing the formation and actions of another peptide of the RAS, angiotensin-(1-7), were published. Since then several publications have shown that angiotensin-(1-7) is as pleiotropic as angiotensin II, influencing the functions of many organs and systems. The identification of the ACE homologue ACE2 and, a few years later, Mas, as a receptor for angiotensin-(1-7) contributed a great deal to establish this peptide as a key player of the RAS. Most of the actions of angiotensin-(1-7) are opposite to those described for angiotensin II. This has led to the concept of two arms of the RAS: one comprising ACE/AngII/AT1R and the other ACE2/Ang-(1-7)/Mas. More recently, we have described the identification of a novel component of the RAS, alamandine, which binds to the Mas-related G protein coupled receptor D. This peptide is formed by decarboxylation of the Asp residue of angiotensin-(1-7), leading to the formation of Ala as the N-terminal amino acid. Alternatively, it can be formed by hydrolysis of Ang A, by ACE2. Its effects include vasorelaxation, central effects similar to those produced by angiotensin-(1-7), blunting of isoproterenol-induced heart fibrosis, and anti-hypertensive action in SHR. The putative enzyme responsible for alamandine formation from angiotensin-(1-7) is under investigation. The identification of this novel component of the RAS opens new venues for understanding its physiological role and opens new putative therapeutic possibilities for treating cardiovascular diseases.

Topics: Angiotensin I; Angiotensin II; Antihypertensive Agents; Cardiovascular Diseases; Humans; Hypertension; Oligopeptides; Peptide Fragments; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Risk Assessment; Sensitivity and Specificity

Topics: Angiotensin I; Angiotensinogen; Animals; Antidepressive Agents; Brain; Injections, Intraventricular; Male; Nerve Tissue Proteins; Oligopeptides; Peptide Fragments; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, G-Protein-Coupled

Sepsis is a frequent cause of kidney injury. The present study investigated whether Alamandine (Ala) could alleviate sepsis-associated renal injury by reducing inflammation and apoptosis. In addition, we investigated downstream signaling pathways modulated by Ala. Studies were performed in mice treated with lipopolysaccharide (LPS) and in the human proximal tubular epithelial cell line HK-2. The increase in serum creatinine, blood urea nitrogen, cystatin C and Fg, and neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in the kidneys of mice treated with LPS were reduced after administration of Ala. Exposure to LPS increased interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) in mice and HK-2 cells, but were reduced after Ala treatment. Furthermore, increased levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9, cleaved poly (ADP-ribose) polymerase (PARP) and Bax and reduced levels of Bcl2 in LPS-treated mice and HK-2 cells were reversed after Ala administration. In addition, LPS increased the levels of p-PI3K/PI3K, p-Akt/Akt, p-ERK/ERK, p-JNK/JNK, p-p38/p38 and p-FoxO1 in HK-2 cells, and all were reversed after Ala administration. These results indicate that Ala could improve renal function and inhibit inflammation and apoptosis in LPS induced sepsis mouse models. We demonstrated that Ala attenuated LPS induced sepsis by inhibiting the PI3K/Akt and MAPK signaling pathways.

Topics: Angiotensin I; Animals; Apoptosis; Cell Line; Dose-Response Relationship, Drug; Humans; Inflammation; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Oligopeptides; Peptide Fragments; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sepsis; Signal Transduction

The understanding of the renin-angiotensin system (RAS) has significantly expanded over the last two decades. The elucidation of angiotensin-converting enzyme 2 (ACE2) that converts angiotensin (Ang) II into Ang (1-7) led to the discovery of the cardio-protective axis of the RAS. In addition, novel components of the system, Angiotensin A (Ang A) and alamandine have been identified. Like Ang (1-7), alamandine is a vasodilator and can counteract the effects of Ang II by increasing nitric oxide release from the endothelium and decreasing nicotinamide adenine dinucleotide phosphate oxidase (NADPH)-related superoxide production. Theoretically, alamandine can be derived from Ang (1-7) by decarboxylation of the N-terminal aspartic acid residue to alanine, but the enzyme responsible for this is still unknown. To date, no human or mammalian enzyme with the assigned decarboxylase activity has been identified. However, several bacterial enzymes capable of converting aspartate to alanine have been reported. Therefore, we hypothesize that a bacterial enzyme, most likely present in the microbiome of the gastrointestinal tract, the heart, or systemic circulation could metabolize Ang II, and/or Ang 1-7, to Ang A and alamandine, respectively, in mammals.

Topics: Angiotensin I; Angiotensin II; Animals; Carboxy-Lyases; Humans; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Receptors, G-Protein-Coupled; Renin-Angiotensin System

Microinjection of alamandine into the hypothalamic paraventricular nucleus (PVN) increased blood pressure and enhanced sympathetic activity. The aim of this study was to determine if superoxide anions modulate alamandine's effects in the PVN. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were recorded in anaesthetized normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Microinjection of alamandine into the PVN increased MAP and RSNA in both WKY rats and SHRs, although to a greater extent in SHRs. These effects were blocked by pretreatment with an alamandine receptor (MrgD) antagonist D-Pro

Topics: Angiotensin I; Animals; Autonomic Pathways; Blood Pressure; Male; NADPH Oxidases; Oligopeptides; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Superoxides; Sympathetic Nervous System

Obesity is associated with an increased risk of diabetes mellitus, hypertension, and renal dysfunction. Angiotensin 1-7 and alamandine are heptameric renin angiotensin system peptide hormones. Further, alamandine levels increase with renal dysfunction. In the cardiovascular system, angiotensin 1-7 and alamandine produce similar improvements and counterbalance angiotensin II in regulating vascular function. We aimed to determine whether the effect of alamandine on leptin expression and secretion in adipocytes was similar to that of angiotensin 1-7.. We studied isolated peri-renal visceral adipose tissue and peri-renal isolated visceral adipocytes from male Wistar rats. Angiotensin II from 0.01 to 10nM had no effect on leptin expression. Angiotensin 1-7 (1 nM) increased leptin secretion and expression, whereas alamandine (1 nM) decreased leptin secretion and expression in adipose tissue and isolated adipocytes and reduced blood leptin levels in vivo. These effects were mediated by Gq, c-Src, p38 mitogen-activated protein, and IκB activation. Additionally, alamandine induced nitric oxide expression via inducible nitric oxidase synthase and plasminogen activator inhibitor 1 expression in adipose tissue and isolated adipocytes.. Angiotensin 1-7 and alamandine produced opposing effects on leptin expression and secretion in adipose tissue. This result suggests that the action of Mas (angiotensin 1-7 receptor) and Mas-related G-protein coupled receptor D in adipocytes exhibited opposing actions similar to angiotensin II type 1 and type 2 receptors.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Angiotensin I; Animals; Cell Separation; CSK Tyrosine-Protein Kinase; GTP-Binding Protein alpha Subunits, Gq-G11; Leptin; Male; MAP Kinase Signaling System; Mice; Models, Biological; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oligopeptides; Peptide Fragments; Plasminogen Activator Inhibitor 1; Rats, Wistar; Receptors, G-Protein-Coupled; src-Family Kinases

Topics: Angiotensin I; Angiotensin II Type 2 Receptor Blockers; Animals; Hypertension; Imidazoles; Male; Oligopeptides; Peptide Fragments; Pyridines; Rats; Receptor, Angiotensin, Type 2; Renin-Angiotensin System

Novel treatments are necessary to reduce the burden of cardiovascular disease (CVD). Alamandine binds to MrgD and is reported to induce vasodilation via stimulation of endothelial nitric oxide synthase (eNOS), but its role in atherogenic blood vessels is yet to be determined. To determine the vasoactive role of alamandine and its precursor AngA in diseased aorta, New Zealand White rabbits were fed a diet containing 1% methionine + 0.5% cholesterol + 5% peanut oil for 4 weeks (MC, n = 5) or control (n = 6). In abdominal aorta, alamandine (1 μM) was added 30 min before a dose-response curve to angiotensin II or AngA (1 nM-1 μM), and immunohistochemistry was used to identify MrgD receptors and eNOS. The thoracic aorta, renal, carotid and iliac arteries were mounted in organ baths. Rings were precontracted with phenylephrine, then a bolus dose of alamandine (1 μM) was added 10 min before a dose-response curve to acetylcholine (0.01 μM-10 μM). The MrgD receptor was localized to normal and diseased aorta and colocalized with eNOS. In control but not diseased blood vessels, alamandine enhanced acetylcholine-mediated vasodilation in the thoracic aorta and the iliac artery (P < 0.05) and reduced it in the renal artery (P < 0.05). In control abdominal aorta, AngA evoked less desensitization than AngII (P < 0.05) and alamandine reduced AngA-mediated vasoconstriction (P < 0.05). In MC, AngA constriction was markedly reduced vs. control (P < 0.05). The vasoactivity of alamandine and AngA are reduced in atherogenesis. Its role in the prevention of CVD remains to be validated.

Topics: Acetylcholine; Angiotensin I; Angiotensins; Animals; Aorta, Abdominal; Aorta, Thoracic; Atherosclerosis; Carotid Arteries; Disease Models, Animal; Dose-Response Relationship, Drug; Iliac Artery; Male; Nitric Oxide Synthase Type III; Oligopeptides; Peptide Fragments; Phenylephrine; Rabbits; Receptors, G-Protein-Coupled; Renal Artery; Vasoconstriction; Vasodilation

The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7).. To characterize a novel component of the RAS, alamandine.. Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines.. The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Antihypertensive Agents; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Drug Discovery; Humans; Male; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Inbred F344; Rats, Inbred SHR; Receptors, G-Protein-Coupled; Renin-Angiotensin System

Topics: Angiotensin I; Animals; Antihypertensive Agents; Drug Discovery; Humans; Male; Oligopeptides; Peptide Fragments; Renin-Angiotensin System