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Molecular and Cellular Endocrinology Jun 2021The identification of an alternate extended form of angiotensin I composed of the first twelve amino acids at the N-terminal of angiotensinogen has generated new... (Review)
Review
The identification of an alternate extended form of angiotensin I composed of the first twelve amino acids at the N-terminal of angiotensinogen has generated new knowledge of the importance of noncanonical mechanisms for renin independent generation of angiotensins. The human sequence of the dodecapeptide angiotensin-(1-12) [N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Va-Ile-COOH] is an endogenous substrate that in the rat has been documented to be present in multiple organs including the heart, brain, kidney, gut, adrenal gland, and the bone marrow. Newer studies have confirmed the existence of Ang-(1-12) as an Ang II-forming substrate in the blood and heart of normal and diseased patients. Studies to-date document that angiotensin II generation from angiotensin-(1-12) does not require renin participation while chymase rather than angiotensin converting enzyme shows high catalytic activity in converting this tissue substrate into angiotensin II directly.
Topics: Adrenal Glands; Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Biocatalysis; Bone Marrow; Brain; Cardiovascular Diseases; Chymases; Gene Expression; Humans; Intestines; Kidney; Myocardium; Peptide Fragments; Rats; Renin-Angiotensin System
PubMed: 33309638
DOI: 10.1016/j.mce.2020.111119 -
Sovremennye Tekhnologii V Meditsine 2021The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at... (Review)
Review
UNLABELLED
The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS). is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2.
RESULTS
By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection.The second participant in the pathogenesis of brain damage in COVID-19 is CD147 - the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Astrocytes; Basigin; Brain; COVID-19; Humans; Peptide Fragments; SARS-CoV-2; Serine Endopeptidases
PubMed: 34796023
DOI: 10.17691/stm2020.12.6.11 -
Journal of Hypertension Aug 2021The branch of the renin--angiotensin system constituting angiotensin-(1-7) [Ang-(1-7)], the Ang II type 2 receptor, the Mas receptors and the Ang-(1-7)-forming enzyme...
OBJECTIVE
The branch of the renin--angiotensin system constituting angiotensin-(1-7) [Ang-(1-7)], the Ang II type 2 receptor, the Mas receptors and the Ang-(1-7)-forming enzyme ACE-2, by counteracting the Ang II type 1 receptor (AT1R)-mediated effects, are held to be cardiovascular protective in several conditions. However, whether Ang-(1-7) and ACE-2 are detectable in human adrenocortical tissues and whether they affect aldosterone and cortisol biosynthesis was unknown.
METHODS
We measured angiotensin peptides with liquid chromatography tandem-mass spectrometry and ACE-2 mRNA with digital droplet (dd)PCR in human aldosterone-producing adenoma (APA) and APA-adjacent tissue obtained from patients with primary aldosteronism. We also investigated the effects of Ang-(1-7) and the ACE-2 activator diminazene aceturate (DIZE) on aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1) gene expression, in the absence or presence of the AT1R antagonist irbesartan, or of the MasR antagonist A779.
RESULTS
APA and APA-adjacent adrenocortical tissues express ACE-2 mRNA and contain detectable amounts of Ang II and Ang-(2-8), but not of Ang I, Ang-(1-5), Ang (3-8) and Ang-(1-7). Under unstimulated and Ang II- stimulated conditions Ang-(1-7) did not blunt CYP11B1 and CYP11B2 mRNA. At supraphysiological concentrations (10-4 mol/l), Ang-(1-7) stimulated both CYP11B1 and CYP11B2 mRNA via the AT1R. The ACE-2 activator DIZE increased by 1.5-fold ACE-2 mRNA but did not blunt Ang II- upregulated CYP11B1 and CYP11B2 expression.
CONCLUSION
These results do not support the hypothesis that the ACE-2/Ang-(1-7)/MasR axis play a protective role by counteracting enhanced aldosterone secretion in humans.
Topics: Adrenal Cortex; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Cytochrome P-450 CYP11B2; Humans; Hydrocortisone; Peptide Fragments; Proto-Oncogene Mas
PubMed: 33657582
DOI: 10.1097/HJH.0000000000002816 -
Frontiers in Immunology 2022Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to... (Review)
Review
Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to secondary brain injuries and delayed cerebral ischemia, further increasing the risk of a poor outcome. In recent years, the renin-angiotensin system (RAS) has been proposed as a target pathway for therapeutic interventions after brain injury. The RAS is a complex system of biochemical reactions critical for several systemic functions, namely, inflammation, vascular tone, endothelial activation, water balance, fibrosis, and apoptosis. The RAS system is classically divided into a pro-inflammatory axis, mediated by angiotensin (Ang)-II and its specific receptor ATR, and a counterbalancing system, presented in humans as Ang-(1-7) and its receptor, MasR. Experimental data suggest that upregulation of the Ang-(1-7)/MasR axis might be neuroprotective in numerous pathological conditions, namely, ischemic stroke, cognitive disorders, Parkinson's disease, and depression. In the presence of SAH, Ang-(1-7)/MasR neuroprotective and modulating properties could help reduce brain damage by acting on neuroinflammation, and through direct vascular and anti-thrombotic effects. Here we review the role of RAS in brain ischemia, with specific focus on SAH and the therapeutic potential of Ang-(1-7).
Topics: Angiotensin I; Angiotensin II; Brain Ischemia; Humans; Peptide Fragments; Subarachnoid Hemorrhage
PubMed: 35355989
DOI: 10.3389/fimmu.2022.841692 -
Hypertension (Dallas, Tex. : 1979) Feb 2022ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A...
ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.
Topics: ADAM17 Protein; Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; COVID-19; Enzyme Activation; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptide Fragments; Prognosis; Prospective Studies; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Renin-Angiotensin System; Respiration, Artificial; Risk; SARS-CoV-2; Treatment Outcome
PubMed: 34844421
DOI: 10.1161/HYPERTENSIONAHA.121.18295 -
Molecular Pharmacology Jan 2021Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in... (Review)
Review
Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions in the peri-ischemic vasculature. This innate vasoprotective mechanism is impaired in certain chronic clinical conditions, which leads to the development of cardiovascular complications. Members of the renin-angiotensin system-angiotensin-converting enzymes (ACEs) ACE and ACE2, angiotensin II (Ang II), Ang-(1-7), and receptors AT1 and Mas-are expressed in vasculogenic progenitor cells derived from humans and rodents. Ang-(1-7), generated by ACE2, is known to produce cardiovascular protective effects by acting on Mas receptor and is considered as a counter-regulatory mechanism to the detrimental effects of Ang II. Evidence has now been accumulating in support of the activation of the ACE2/Ang-(1-7)/Mas receptor pathway by pharmacologic or molecular maneuvers, which stimulates mobilization of progenitor cells from bone marrow, migration to areas of vascular damage, and revascularization of ischemic areas in pathologic conditions. This minireview summarizes recent studies that have enhanced our understanding of the physiology and pharmacology of vasoprotective axis in bone marrow-derived progenitor cells in health and disease. SIGNIFICANCE STATEMENT: Hematopoietic stem progenitor cells (HSPCs) stimulate revascularization of ischemic areas. However, the reparative potential is diminished in certain chronic clinical conditions, leading to the development of cardiovascular diseases. ACE2 and Mas receptor are key members of the alternative axis of the renin-angiotensin system and are expressed in HSPCs. Accumulating evidence points to activation of ACE2 or Mas receptor as a promising approach for restoring the reparative potential, thereby preventing the development of ischemic vascular diseases.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Hematopoietic Stem Cells; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Signal Transduction; Stem Cells
PubMed: 32321734
DOI: 10.1124/mol.119.117580 -
The American Journal of Pathology Oct 2020Coronavirus disease 2019 has markedly varied clinical presentations, with most patients being asymptomatic or having mild symptoms. However, severe acute respiratory... (Review)
Review
Coronavirus disease 2019 has markedly varied clinical presentations, with most patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by ACE 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury. ACE2 is identified as an essential receptor for SARS-CoV-2 to enter the cell. The binding of ACE2 and SARS-CoV-2 leads to the exhaustion and down-regulation of ACE2. The interaction and imbalance between ACE and ACE2 result in an unopposed angiotensin II. Considering that the ACE insertion (I)/deletion (D) gene polymorphism contributes to the ACE level variability in general population, in which mean ACE level in DD carriers is approximately twice that in II carriers, we propose a hypothesis of genetic predisposition to severe lung injury in patients with coronavirus disease 2019. It is plausible that the ACE inhibitors and ACE receptor blockers may have the potential to prevent and to treat the acute lung injury after SARS-CoV-2 infection, especially for those with the ACE genotype associated with high ACE level.
Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Betacoronavirus; COVID-19; Coronavirus Infections; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Lung Injury; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Polymorphism, Genetic; Receptors, Virus; Renin-Angiotensin System; SARS-CoV-2
PubMed: 32735889
DOI: 10.1016/j.ajpath.2020.07.009 -
American Journal of Physiology. Heart... May 2019Thirty 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,... (Review)
Review
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 (ATR), in contrast to the other, the ANG II type 1 receptor (ATR), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1-7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled "The Renin-Angiotensin System: Going Beyond the Classical Paradigms," in which the signaling and physiological actions of ANG-(1-7), ACE2, ATR, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.
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
PubMed: 30707614
DOI: 10.1152/ajpheart.00723.2018 -
Clinical Science (London, England :... Jan 2021The two axes of the renin-angiotensin system include the classical ACE/Ang II/AT1 axis and the counter-regulatory ACE2/Ang-(1-7)/Mas1 axis. ACE2 is a multifunctional... (Review)
Review
The two axes of the renin-angiotensin system include the classical ACE/Ang II/AT1 axis and the counter-regulatory ACE2/Ang-(1-7)/Mas1 axis. ACE2 is a multifunctional monocarboxypeptidase responsible for generating Ang-(1-7) from Ang II. ACE2 is important in the vascular system where it is found in arterial and venous endothelial cells and arterial smooth muscle cells in many vascular beds. Among the best characterized functions of ACE2 is its role in regulating vascular tone. ACE2 through its effector peptide Ang-(1-7) and receptor Mas1 induces vasodilation and attenuates Ang II-induced vasoconstriction. In endothelial cells activation of the ACE2/Ang-(1-7)/Mas1 axis increases production of the vasodilator's nitric oxide and prostacyclin's and in vascular smooth muscle cells it inhibits pro-contractile and pro-inflammatory signaling. Endothelial ACE2 is cleaved by proteases, shed into the circulation and measured as soluble ACE2. Plasma ACE2 activity is increased in cardiovascular disease and may have prognostic significance in disease severity. In addition to its enzymatic function, ACE2 is the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV) and SARS-Cov-2, which cause SARS and coronavirus disease-19 (COVID-19) respectively. ACE-2 is thus a double-edged sword: it promotes cardiovascular health while also facilitating the devastations caused by coronaviruses. COVID-19 is associated with cardiovascular disease as a risk factor and as a complication. Mechanisms linking COVID-19 and cardiovascular disease are unclear, but vascular ACE2 may be important. This review focuses on the vascular biology and (patho)physiology of ACE2 in cardiovascular health and disease and briefly discusses the role of vascular ACE2 as a potential mediator of vascular injury in COVID-19.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Vessels; COVID-19; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; SARS-CoV-2; Vascular Diseases
PubMed: 33511992
DOI: 10.1042/CS20200480 -
Peptides Jun 2022Vascular aging is a complex and multifaceted process that provokes profound molecular, structural, and functional changes in the vasculature. Eventually, these profound...
Vascular aging is a complex and multifaceted process that provokes profound molecular, structural, and functional changes in the vasculature. Eventually, these profound aging alterations make arteries more prone to vascular disease, including hypertension, atherosclerosis and other arterial complications that impact the organism beyond the cardiovascular system and accelerate frailty. For these reasons, preventing or delaying the hallmarks of vascular aging is nowadays a major health goal, especially in our aged societies. In this context, angiotensin(Ang)-(1-7), a major player of the protective branch of the renin-angiotensin system, has gained relevance over recent years as growing knowledge on its anti-aging properties is being unveiled. Here, we briefly review the main actions of Ang-(1-7) against vascular aging. These include protection against vascular cell senescence, anti-inflammatory and antioxidant effects together with the induction of cytoprotective systems. Ang-(1-7) further ameliorates endothelial dysfunction, a hallmark of vascular aging and disease, attenuates fibrosis and calcification and promotes protective angiogenesis and repair. Although further research is needed to better understand the anti-aging properties of Ang-(1-7) on the vasculature, this heptapeptide arises as a promising pharmacological tool for preventing vascular aging and frailty.
Topics: Aged; Aging; Angiotensin I; Angiotensin II; Frailty; Humans; Peptide Fragments; Renin-Angiotensin System
PubMed: 35231551
DOI: 10.1016/j.peptides.2022.170775