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1.
Int J Mol Sci ; 23(6)2022 Mar 13.
Article in English | MEDLINE | ID: covidwho-1745035

ABSTRACT

Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1-7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Inflammasomes/metabolism , Ischemic Stroke/metabolism , Proteins/metabolism , Angiotensin I/metabolism , COVID-19/complications , COVID-19/virology , Humans , Ischemic Stroke/complications , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Peptide Fragments/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Signal Transduction
2.
Life Sci ; 293: 120324, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1616648

ABSTRACT

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Renin-Angiotensin System/physiology , Serine Endopeptidases/metabolism , Adult , Age Factors , Aged , Alveolar Epithelial Cells/chemistry , Alveolar Epithelial Cells/drug effects , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Female , Humans , Lung/chemistry , Lung/drug effects , Lung/metabolism , Male , Middle Aged , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects , Retrospective Studies , Serine Endopeptidases/analysis , Smoking/metabolism , Smoking/pathology
3.
Rev Med Virol ; 31(5): 1-12, 2021 09.
Article in English | MEDLINE | ID: covidwho-1575376

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumour necrosis factor-α-converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1-7), to balance the renin angiotensin system. Membrane-bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS-CoV-2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non-primed virus-sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II-angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , COVID-19/virology , Comorbidity , Humans , Peptide Fragments/metabolism , SARS-CoV-2/physiology
4.
J Renin Angiotensin Aldosterone Syst ; 2021: 6824259, 2021.
Article in English | MEDLINE | ID: covidwho-1546597

ABSTRACT

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.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Oligopeptides/therapeutic use , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , COVID-19/metabolism , Humans , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects
5.
Int J Mol Sci ; 22(23)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542585

ABSTRACT

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1-7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1-7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.


Subject(s)
Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Fibrosis/metabolism , Peptide Fragments/metabolism , /metabolism , Cannabis , Cigarette Smoking , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Inflammation , Lung/pathology , Pandemics , Respiration, Artificial , Respiratory Distress Syndrome , Respiratory Insufficiency/metabolism , Risk Factors , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
6.
Sovrem Tekhnologii Med ; 12(6): 98-108, 2021.
Article in English | MEDLINE | ID: covidwho-1527052

ABSTRACT

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). The aim of the study 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.


Subject(s)
Astrocytes/metabolism , Brain/metabolism , COVID-19/metabolism , SARS-CoV-2/metabolism , Angiotensin I/metabolism , Angiotensin II/analogs & derivatives , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Basigin , Humans , Peptide Fragments/metabolism , Serine Endopeptidases/metabolism
7.
Biosci Rep ; 41(12)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1506391

ABSTRACT

The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Lung/metabolism , Peptidyl-Dipeptidase A/metabolism , ADAM17 Protein/metabolism , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Down-Regulation , Female , Male , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/genetics , RNA, Messenger/metabolism , Rats , Rats, Inbred SHR , Rats, Wistar , Sex Characteristics
8.
Mol Cell Biochem ; 477(1): 225-240, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1469743

ABSTRACT

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.


Subject(s)
Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/diet therapy , Peptide Fragments/metabolism , /metabolism , Cardiovascular Diseases/pathology , Cardiovascular Diseases/virology , Dietary Proteins/pharmacology , Flavonoids/pharmacology , Humans , Lung/pathology , Lung/virology , Plant Oils/pharmacology , Polyphenols/pharmacology , Terpenes/pharmacology , Virus Internalization , Vitamins/pharmacology
10.
Adv Biol Regul ; 81: 100820, 2021 08.
Article in English | MEDLINE | ID: covidwho-1351735

ABSTRACT

The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several "converging" evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1-7 and Ang 1-9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.


Subject(s)
ADAM17 Protein/biosynthesis , Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , ADAM17 Protein/antagonists & inhibitors , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19/drug therapy , Gene Expression Regulation, Enzymologic , Humans , Peptide Fragments/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Up-Regulation
11.
Histol Histopathol ; 36(11): 1125-1131, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1278774

ABSTRACT

The brain has its own intrinsic renin-angiotensin system (RAS) with all its components present in the central nervous system (CNS). Recent data demonstrate that also the main components of the angiotensin concerting enzyme 2 (ACE2) system (at least ACE2 itself, as well as the biologically active angiotensin (1-7) and its cognate receptor Mas) are expressed in the brain. Aside from these members, alamadine and MrgD are discussed as further members that have neuro-active roles in the CNS. Little is known about the possible functions of MrgD within the brain. Concerning angiotensin (1-7) acting through the Mas receptor, data were accumulating that this system is involved in numerous processes contributing to neuronal plasticity and even learning and memory. Malfunctions in the brain ACE2 system are associated with disturbances in neuronal plasticity. Since SARS-CoV-2 has a high affinity towards ACE2, Neuro-Covid may directly or indirectly depend on a disturbed balance in the ACE2 derived angiotensin system in the brain. Since the ACE2 system in the brain is far from being understood, a deeper understanding of e.g. the angiotensin (1-7) / Mas system is needed, especially with regard to the roles of angiotensin (1-7) in neuronal plasticity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain/enzymology , COVID-19/complications , COVID-19/enzymology , Nervous System Diseases/enzymology , Nervous System Diseases/etiology , Angiotensin I/genetics , Angiotensin I/metabolism , Animals , Humans , Peptide Fragments/genetics , Peptide Fragments/metabolism , Receptors, G-Protein-Coupled/genetics
12.
Int J Mol Sci ; 22(8)2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1186971

ABSTRACT

The cumulative number of cases in the current global coronavirus disease 19 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has exceeded 100 million, with the number of deaths caused by the infection having exceeded 2.5 million. Recent reports from most frontline researchers have revealed that SARS-CoV-2 can also cause fatal non-respiratory conditions, such as fatal cardiovascular events. One of the important mechanisms underlying the multiple organ damage that is now known to occur during the acute phase of SARS-CoV-2 infection is impairment of vascular function associated with inhibition of angiotensin-converting enzyme 2. To manage the risk of vascular dysfunction-related complications in patients with COVID-19, it would be pivotal to clearly elucidate the precise mechanisms by which SARS-CoV-2 infects endothelial cells to cause vascular dysfunction. In this review, we summarize the current state of knowledge about the mechanisms involved in the development of vascular dysfunction in the acute phase of COVID-19.


Subject(s)
COVID-19/complications , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Acute Disease , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Arteries/physiology , Arteries/physiopathology , Humans , Morbidity , Peptide Fragments/metabolism , Vascular Stiffness
13.
Clin Sci (Lond) ; 135(2): 387-407, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1054073

ABSTRACT

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.


Subject(s)
Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Vascular Diseases/virology , Animals , Blood Vessels/enzymology , Humans , Receptor, Angiotensin, Type 2/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , Vascular Diseases/metabolism
14.
Eur Respir J ; 57(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1041881

ABSTRACT

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.


Subject(s)
Acute Lung Injury/genetics , Angiotensin I/metabolism , COVID-19/epidemiology , Capillary Permeability/genetics , Endothelium, Vascular/metabolism , Estrogens/metabolism , Lung/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Respiratory Distress Syndrome/epidemiology , Acute Lung Injury/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin I/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Capillary Permeability/drug effects , Child , Electric Impedance , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Estradiol/pharmacology , Female , Humans , In Vitro Techniques , Lung/drug effects , Male , Mice , Mice, Knockout , Middle Aged , Ovariectomy , Peptide Fragments/pharmacology , Platelet Activating Factor/pharmacology , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , SARS-CoV-2 , Sex Distribution , Sex Factors , Up-Regulation , Young Adult
15.
Clin Sci (Lond) ; 134(22): 3047-3062, 2020 11 27.
Article in English | MEDLINE | ID: covidwho-1030462

ABSTRACT

Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin-angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.


Subject(s)
Angiotensin I/metabolism , COVID-19/metabolism , Muscle, Skeletal/enzymology , Peptide Fragments/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/enzymology , COVID-19/genetics , Humans , SARS-CoV-2/physiology
16.
Peptides ; 137: 170477, 2021 03.
Article in English | MEDLINE | ID: covidwho-1001641

ABSTRACT

After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the renin-angiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT1 Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-Asp1Ang II, 2-8 heptapeptide) and Ang IV (des-Asp1des-Arg2Ang II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest Km) for Ang III, followed by Ang II ∼ Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 µM. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensins/metabolism , Peptides/metabolism , Recombinant Proteins/metabolism , Aminopeptidases/genetics , Aminopeptidases/metabolism , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin II/analogs & derivatives , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/genetics , Humans , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptides/genetics , Peptidyl-Dipeptidase A/genetics , Recombinant Proteins/genetics , Renin-Angiotensin System/genetics , Zinc/pharmacology
17.
Bioessays ; 43(3): e2000112, 2021 03.
Article in English | MEDLINE | ID: covidwho-985954

ABSTRACT

This renin-angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues. Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS-related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle. RAS and stress accumulation: While prorenin is active after binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance. Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Hypertension/genetics , Renin-Angiotensin System/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Aged , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/mortality , COVID-19/virology , Gene Expression Regulation , Humans , Hypertension/metabolism , Hypertension/mortality , Hypertension/virology , Lung/metabolism , Lung/pathology , Lung/virology , Myocardium/metabolism , Myocardium/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/genetics , Receptor, Angiotensin, Type 2/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Renin/genetics , Renin/metabolism , Signal Transduction , Survival Analysis
18.
Eur Rev Med Pharmacol Sci ; 24(23): 12609-12622, 2020 12.
Article in English | MEDLINE | ID: covidwho-995022

ABSTRACT

OBJECTIVE: In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease. MATERIALS AND METHODS: PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm. RESULTS: The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed. CONCLUSIONS: The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.


Subject(s)
Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cardiomyopathies/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/physiopathology , Liver Cirrhosis/metabolism , Systemic Inflammatory Response Syndrome/metabolism , Thrombosis/metabolism , Angiotensin I/metabolism , Atrial Fibrillation/metabolism , Atrial Fibrillation/physiopathology , Blood Coagulation , COVID-19/pathology , COVID-19/physiopathology , Capillary Permeability , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Cytokine Release Syndrome/physiopathology , Cytokines/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Fibrosis , Humans , Liver Cirrhosis/pathology , Liver Cirrhosis/physiopathology , Myocarditis/metabolism , Myocarditis/pathology , Myocarditis/physiopathology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , Systemic Inflammatory Response Syndrome/physiopathology , Thrombosis/physiopathology , Virus Internalization
19.
Am J Pathol ; 190(10): 2013-2017, 2020 10.
Article in English | MEDLINE | ID: covidwho-796807

ABSTRACT

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.


Subject(s)
Coronavirus Infections , Genetic Predisposition to Disease , Lung Injury/etiology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/physiopathology , Gene Frequency , Genotype , Humans , Lung Injury/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/physiopathology , Polymorphism, Genetic , Receptors, Virus/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/physiology , SARS-CoV-2
20.
Adv Chronic Kidney Dis ; 27(5): 404-411, 2020 09.
Article in English | MEDLINE | ID: covidwho-722379

ABSTRACT

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.


Subject(s)
Acute Lung Injury/metabolism , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/metabolism , Hypertension/drug therapy , Acute Lung Injury/epidemiology , Acute Lung Injury/immunology , Angiotensin I/immunology , Angiotensin I/metabolism , Angiotensin II/immunology , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/immunology , COVID-19/epidemiology , COVID-19/immunology , Comorbidity , Humans , Hypertension/epidemiology , Hypertension/metabolism , JNK Mitogen-Activated Protein Kinases/immunology , JNK Mitogen-Activated Protein Kinases/metabolism , Lung/immunology , Lung/metabolism , MAP Kinase Signaling System , Peptide Fragments/immunology , Peptide Fragments/metabolism , Protective Factors , Receptors, Coronavirus/immunology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , Risk Factors , SARS-CoV-2 , Up-Regulation
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