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2.
Theranostics ; 10(16): 7448-7464, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32642005

RESUMO

The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Receptores Virais/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/química , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Modelos Animais de Doenças , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Camundongos , Modelos Biológicos , Pandemias , Pneumonia Viral/terapia , Sistema Renina-Angiotensina/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Nanomedicina Teranóstica , Vacinas Virais/isolamento & purificação , Internalização do Vírus
3.
Medicine (Baltimore) ; 99(27): e20943, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629698

RESUMO

Angiotensin II mediates exercise-induced hypertension (EIH), which adversely impacts future cardiovascular health. There is paucity of data on the association between EIH and angiotensin II in well-trained middle-aged marathoners. Therefore, we investigated the renin-angiotensin-aldosterone-system and total nitric oxide activity in middle-aged marathoners with EIH.Seventy middle-aged marathoners were divided into 3 groups: normal blood pressure ([NBPG] [n = 21]), EIH group ([EIHG] [n = 35]), and complex hypertension group ([CHG] [n = 14]). We defined NBPG as resting systolic BP/diastolic BP (SBP/DBP) of ≤140/90 mm Hg and maximal exercise SBP of ≤210 mm Hg, EIHG as resting SBP/DBP ≤140/90 mm Hg and maximal exercise SBP of ≥210 mm Hg, and CHG as resting SBP/DBP ≥140/90 mm Hg and maximal exercise SBP of ≥210 mm Hg. Renin-angiotensin-aldosterone-system and NO levels were measured before and 30 minutes after the graded exercise test.Renin level was elevated while angiotensin level was reduced after 30 minutes of graded exercise test. There was no change in angiotensin I and angiotensin converting enzyme levels. Comparing the groups, renin level was only elevated in the CHG during recovery, while aldosterone level was higher than the baseline level in the recovery phase in all groups. Angiotensin I level remained unchanged in all groups. Angiotensin II level reduced significantly in the NBPG group but remained at the baseline in the EIHG and CHG groups. NO level was unchanged in the NBPG group but reduced in the EIHG and CHG groups after exercise. At 3 minutes of recovery, SBP was the highest in the NBPG group, followed by the EIHG and CHG groups (P < .05).In conclusion, angiotensin II activity and reduced NO level are associated with EIH in middle-aged long-distance runners. Angiotensin II inhibitors may; therefore, be the more appropriate antihypertensive medication for runners with EIH.


Assuntos
Angiotensina II/sangue , Exercício Físico , Hipertensão/fisiopatologia , Óxido Nítrico/sangue , Corrida , Adulto , Pressão Sanguínea , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina
4.
J Stroke Cerebrovasc Dis ; 29(8): 104941, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689643

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat. Some COVID-19 patients have exhibited widespread neurological manifestations including stroke. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19. COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm. Recent studies suggest that axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia. The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes. ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain. The aim of this review is to provide insights into the clinical manifestations and pathophysiological mechanisms of stroke in COVID-19 patients. SARS-CoV-2 can down-regulate ACE2 and, in turn, overactivate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain. The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.


Assuntos
Betacoronavirus/patogenicidade , Encéfalo/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Encefalite Viral/fisiopatologia , Pneumonia Viral/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Betacoronavirus/metabolismo , Coagulação Sanguínea , Encéfalo/metabolismo , Encéfalo/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Encefalite Viral/epidemiologia , Encefalite Viral/metabolismo , Encefalite Viral/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/virologia , Vasodilatação , Virulência
7.
Nat Med ; 26(7): 1017-1032, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32651579

RESUMO

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Especificidade de Órgãos , Pneumonia Viral/patologia , Imunidade Adaptativa/fisiologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Progressão da Doença , Endotélio Vascular/patologia , Endotélio Vascular/virologia , Humanos , Inflamação/etiologia , Inflamação/patologia , Inflamação/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Sistema Renina-Angiotensina/fisiologia , Trombose/etiologia , Trombose/patologia , Trombose/virologia , Internalização do Vírus
8.
Pharmacol Res Perspect ; 8(4): e00623, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32658389

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS-CoV-2 and SARS-CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID-19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesis of COVID-19 and potential therapeutic targets, focusing on the role of the renin-angiotensin-aldosterone system.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Medicina Baseada em Evidências , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/uso terapêutico , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos
11.
J Physiol Pharmacol ; 71(2)2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32633235

RESUMO

COVID-19, which is caused by the single-stranded RNA severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has introduced significant therapeutic dilemmas in several areas. One of these is concern regarding the use of renin-angiotensin system (RAS) inhibitors. Dysfunction of the RAS has been observed in COVID-19 patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs), are associated with improved or worse clinical outcomes, remains unclear. RAS inhibitors are currently widely used in the treatment of hypertension. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with co-morbidities such as hypertension, coronary heart disease, and diabetes mellitus, particularly in the elderly. Therefore, several recently published research papers have focused on the management of hypertension during the COVID-19 pandemic, as this co-morbidity was found to be the most common in patients with coronavirus infections. SARS-CoV-2 viral surface protein is known to attach angiotensin converting enzyme-2 (ACE-2) on the cell membrane to facilitate viral entry into the cytoplasm. While the SARS-CoV-2 viral load remains the highest in upper respiratory tract of COVID-19 patients, it has also been reported in multiple sites in COVID-19, and patients not infrequently require the Intensive Care Units (ICU) admission. However, despite the theoretical concerns of possible increased ACE2 expression by RAS blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection, and indeed they have been shown to be beneficial in some animal studies. In this review we summarise the pathophysiology of the interaction between RAS, ACEIs/ARBs inhibitors and COVID-19, and conclude, on the basis of current data, that RAS blockade should be maintained during the current coronavirus pandemic.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Humanos , Hipertensão/tratamento farmacológico , Pandemias , Pneumonia Viral/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos
13.
Cells ; 9(7)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660065

RESUMO

The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1-9 and Ang 1-7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Endotélio Vascular/metabolismo , Pneumonia Viral/patologia , Sistema Renina-Angiotensina , Angiotensina I/metabolismo , Betacoronavirus/isolamento & purificação , Moléculas de Adesão Celular/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Transdução de Sinais
14.
J Renin Angiotensin Aldosterone Syst ; 21(2): 1470320320928872, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32490715

RESUMO

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus family member that triggers a respiratory disease similar to severe acute respiratory syndrome coronavirus (SARS-CoV). SARS-CoV and SARS-CoV-2 are very similar to each other in many respects, such as structure, genetics, and pathobiology. We hypothesized that coronaviruses could affect pulmonary tissues via integration with the critical immune genes after their interaction with renin-angiotensin system (RAS) elements. The aim of the present bioinformatics study was to assess expression changes of the RAS and non-RAS genes, particularly immune response genes, in the lung epithelial cells after infection with SARS-CoV. METHODS: Linear regression, hierarchical clustering, pathway analysis, and network analysis were performed using the E-GEOD-17400 data set. RESULTS: The whole-genome expression data of the lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were analyzed, and a total of 15 RAS family and 29 immune genes were found to be highly correlated with the exposure time to the virus in the studied groups. CONCLUSION: RAS genes are important at the initiation of the infections caused by coronavirus family members and may have a strong relationship with the exchange of immune genes in due course following the infection.


Assuntos
Betacoronavirus/fisiologia , Brônquios/patologia , Infecções por Coronavirus/genética , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Inflamação/genética , Pneumonia Viral/genética , Sistema Renina-Angiotensina/genética , Análise por Conglomerados , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genoma Humano , Humanos , Inflamação/patologia , Modelos Lineares , Pandemias , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Cardiol Rev ; 28(4): 213-216, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32496364

RESUMO

When the coronavirus disease 2019 (COVID-19) wreaked an unprecedented havoc of an escalating number of deaths and hospitalization in the United States, clinicians were faced with a myriad of unanswered questions, one of the them being the implication of the renin-angiotensin-aldosterone system in patients with COVID-19. Animal data and human studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) increase the expression of ACE2. ACE2 is an enzyme found in the heart, kidney, gastrointestinal tract, and lung and is a coreceptor for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV2), the virus responsible for COVID-19. Therefore, one can speculate that discontinuing ACE inhibitor or ARB therapy may lead to decreased ACE2 expression, thereby attenuating the infectivity of SARS-CoV-2, and mitigating the disease progression of COVID-19. However, several studies have also shown that ACE2 exhibits reno- and cardioprotection and preserves lung function in acute respiratory distress syndrome, which would favor ACE inhibitor or ARB therapy. This article is to examine and summarize the 2 opposing viewpoints and provide guideline recommendations to support the use or discontinuation of ACE inhibitors and ARBs in patients with COVID-19.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Guias de Prática Clínica como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia
18.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(5): 613-617, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32576357

RESUMO

2019 Novel coronavirus (2019-nCoV) destroys angiotensin converting enzyme 2 (ACE2) and breaks the balance of renin-angiotension system (RAS) by interacting with ACE2. The imbalance of RAS takes part in the development of organ injury of different systems through pro-inflammation, oxidative stress, cell proliferation and so on. 2019-nCoV not only attacks the lung, but also influences many other systems. It is speculated that RAS imbalance plays an important role in the development of multi-organ dysfunction caused by 2019-nCoV, and the usage of angiotensin converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) may become a new treatment of 2019-nCoV-related organ injury. Further studies are need to confirm the relationship between coronavirus infection, multi-organ injury and RAS imbalance.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Humanos , Renina , Sistema Renina-Angiotensina
19.
Endocrine ; 68(3): 479-484, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542429

RESUMO

With the emergence of the Novel Coronavirus (2019-nCoV), researchers worldwide have started detecting the probable pathogenesis of the disease. The renin-angiotensin system (RAS) and angiotensin-converting enzymes have received a good deal of attention as possible pathways involved in 2019-nCoV pathogenesis. As the experiments seeking to find potential medications acting on these pathways are being conducted in the early phases, having an ecological worldview on the relationship between the prevalence of COVID-19 disease and the genetic differences in the genes involved in the RAS system could be valuable for the field. In this regard, we conducted a meta-analysis study of the prevalence of ACE (I/D) genotype in countries most affected by the COVID-19. In the meta-analysis, 48,758 healthy subjects from 30 different countries were evaluated in 116 studies, using the Comprehensive Meta-analysis software. The I/D allele frequency ratio was pooled by a random-effect model. The COVID-19 prevalence data of death and recovery rates were evaluated as the latitudes for the meta-regression analysis. Our results demonstrated that with the increase of the I/D allele frequency ratio, the recovery rate significantly increased (point estimate: 0.48, CI 95%: 0.05-0.91, p = 0.027). However, there was no significant difference in the case of death rate (point estimate: 1.74, CI 95%: 4.5-1.04, p = 0.22). This ecological perspective coupled with many limitations does not provide a direct clinical relevance between the COVID-19 and RAS system, but it shows potential pathophysiological associations. Our results raise concerns about ethnic and genetic differences that could affect the effectiveness of the currently investigated RAS-associated medications in different regions.


Assuntos
Betacoronavirus , Infecções por Coronavirus/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Polimorfismo Genético/genética , Sistema Renina-Angiotensina/genética , Infecções por Coronavirus/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Humanos , Pandemias , Pneumonia Viral/epidemiologia
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