ACE2 Is an Adjacent Element of Atherosclerosis and COVID-19 Pathogenesis

COVID-19 is a highly contagious new infection caused by the single-stranded RNA Sars-CoV-2 virus. For the first time, this infection was recorded in December 2019 in the Chinese province of Wuhan. The virus presumably crossed the interspecies barrier and passed to humans from a bat. Initially, the disease was considered exclusively in the context of damage to the respiratory system, but it quickly became clear that the disease also entails serious consequences from various systems, including the cardiovascular system. Among these consequences are myocarditis, myocardial damage, subsequent heart failure, myocardial infarction, and Takotsubo syndrome. On the other hand, clinical data indicate that the presence of chronic diseases in a patient aggravates the course and outcome of coronavirus infection. In this context, the relationship between COVID-19 and atherosclerosis, a condition preceding cardiovascular disease and other disorders of the heart and blood vessels, is particularly interesting. The renin-angiotensin system is essential for the pathogenesis of both coronavirus disease and atherosclerosis. In particular, it has been shown that ACE2, an angiotensin-converting enzyme 2, plays a key role in Sars-CoV-2 infection due to its receptor activity. It is noteworthy that this enzyme is important for the normal functioning of the cardiovascular system. Disruptions in its production and functioning can lead to various disorders, including atherosclerosis.

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TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection

10.1101/2020.02.27.967588 ◽

2020 ◽

Cited By ~ 3

Author(s):

Xiaoyang Ji ◽

Chunming Zhang ◽

Yubo Zhai ◽

Zhonghai Zhang ◽

Chunli Zhang ◽

...

Keyword(s):

Large Scale ◽

Renin Angiotensin System ◽

Gene Interaction ◽

Global Perspective ◽

Pathological Changes ◽

Processing Efficiency ◽

Inference System ◽

Angiotensin Converting Enzyme 2 ◽

Functional Changes ◽

Coronavirus Infection

AbstractFaced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the “coronavirus” should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

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Russian Medical Society for Arterial Hypertension Expert Consensus: Hypertension and COVID-19

Systemic Hypertension ◽

10.26442/2075082x.2020.3.200362 ◽

2020 ◽

Vol 17 (3) ◽

pp. 35-41

Author(s):

Irina E. Chazova ◽

Natalia V. Blinova ◽

Vera A. Nevzorova ◽

Juliya V. Zhernakova ◽

Mikhail P. Savenkov ◽

...

Keyword(s):

Arterial Hypertension ◽

Medical Society ◽

Target Cells ◽

The Novel ◽

Angiotensin Converting Enzyme 2 ◽

High Prevalence ◽

Coronavirus Infection ◽

Novel Coronavirus ◽

The Relationship ◽

Russian Medical

The novel coronavirus infection (COVID-19) caused by the b-coronavirus SARS-CoV-2, and leads to acute respiratory distress-syndrome, has affected more than nineteen million people worldwide, resulting in 0.7 million deaths as of August 2020. The fact that the virus uses angiotensin-converting enzyme 2 as a receptor for entering the target cell, and the high prevalence of hypertension and other cardiovascular diseases among patients with COVID-19, have caused serious discussions on the management of such patients. This consensus of experts from the Russian Medical Society for Arterial Hypertension analyzed the existing data on the relationship between COVID-19 and hypertension, the pathophysiological aspects of the penetration of the virus into target cells and the use of renin-angiotensin-aldosterone system inhibitors in patients with hypertension and COVID-19.

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Downregulation of Membrane-bound Angiotensin Converting Enzyme 2 (ACE2) Receptor has a Pivotal Role in COVID-19 Immunopathology

Current Drug Targets ◽

10.2174/1389450121666201020154033 ◽

2020 ◽

Vol 21 ◽

Author(s):

Cristina Vieira ◽

Lucas Nery ◽

Ludimila Martins ◽

Luiz Jabour ◽

Raphael Dias ◽

...

Keyword(s):

Immune System ◽

Angiotensin Ii ◽

Renin Angiotensin System ◽

Underlying Mechanism ◽

Receptor Expression ◽

Immune Functions ◽

Angiotensin Converting Enzyme 2 ◽

Membrane Bound ◽

The Relationship ◽

Corona Viruses

Background:: The Coronavirus Disease 2019 (COVID-19) is becoming the major health issue in recent human history with thousands of deaths and millions of cases worldwide. Newer research and old experience with other corona-viruses highlighted a probable underlying mechanism of disturbance of the renin-angiotensin system (RAS) that is associ-ated with intrinsic effects of SARS-CoV-2 infection Objective:: In this review, we aimed to describe the intimate connections between the RAS components, the immune system and COVID-19 pathophysiology. Methods:: This non-systematic review article summarizes recent evidence on the relationship between COVID-19 and the RAS. Results:: Several studies have indicated that the downregulation of membrane-bound ACE2 may exert a key role for the impairment of immune functions and for COVID-19 patients’ outcome. The downregulation may occur by distinct mecha-nisms, particularly: (1) the shedding process induced by SARS-CoV-2 fusion pathway, which reduces the amount of mem-brane-bound ACE2, stimulating more shedding by the high levels of Angiotensin II; (2) the endocytosis of ACE2 receptor with the virus itself and (3) by the interferon inhibition caused by SARS-CoV-2 effects on immune system, which leads to reduction of ACE2 receptor expression. Conclusion:: Recent research provides evidence of a reduction of the components of the alternative RAS axis, including ACE2 and Angiotensin-(1-7). In contrast, increased levels of Angiotensin II can activate the AT1 receptor in several organs. Consequently, increased inflammation, thrombosis and angiogenesis occur in patients infected with SARS-COV-2. Atten-tion should be paid to the interactions of the RAS and COVID-19, mainly in the context of novel vaccines and proposed medications.

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Topical issues of cardiovascular disease in patients with new coronoviral infection COVID-19. Clinical and morphological study

Russian Military Medical Academy Reports ◽

10.17816/rmmar81196 ◽

2021 ◽

Vol 40 (2) ◽

pp. 63-68

Author(s):

Elizaveta V. Zbyshevskaya ◽

Tatyana I. Makeeva ◽

Fatima I. Bitakova ◽

Marina N. Bakholdina ◽

Elena V. Sivtsova ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Disease ◽

Acute Myocardial Infarction ◽

Pulmonary Embolism ◽

Cardiovascular System ◽

Histological Study ◽

Clinical Manifestations ◽

Study Results ◽

Coronavirus Infection ◽

The Relationship

In about 30% of cases, Sars-CoV-2 pneumonia is complicated by damage to the cardiovascular system myocardial infarction, pulmonary embolism, strokes, which are often fatal. There is still little data on the relationship between clinical manifestations and structural changes in the cardiovascular system during a new coronavirus infection. The material for the study was the data of the case histories and autopsies of 185 patients suffering from COVID-19 infection in the period SeptemberDecember 2020. In the deceased patients, a higher percentage of lung tissue damage was recorded on CT data, and a low level of oxygen saturation at the time of hospitalization. Most of the patients had a history of cardiovascular disease, diabetes mellitus, chronic kidney disease, and cancer. The pronounced course of systemic immune inflammation was manifested by a high average level of indicators such as D-dimmer, ferritin, C-reactive protein and fibrinogen. Among the causes of death, respiratory failure prevailed against the background of infectious-toxic shock. Damage to the cardiovascular system was manifested by the development of acute myocardial infarction, pulmonary embolism, stroke. Evaluation of the data of postmortem examination revealed a higher prevalence of stroke and a lower incidence of pulmonary embolism and acute myocardial infarction. In a histological study, damage to the cardiovascular system is represented by direct damage to the myocardium in the form of microcytolysis of cardiomyocytes with the development of necrotic areas. The data obtained from the analysis of the study results allow us to draw conclusions about the relationship between the severity of the course of a new coronavirus infection and the frequency of damage to the cardiovascular system, as well as make assumptions about individual links in the pathogenesis of cardiovascular disease in COVID-19 (1 figure, 2 tables, bibliography: 10 refs).

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Mechanisms of Damage to the Cardiovascular System in COVID-19

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1474 ◽

2021 ◽

Vol 76 (3) ◽

pp. 287-297

Author(s):

Alexandr Y. Fisun ◽

Yuriy V. Lobzin ◽

Dmitry V. Cherkashin ◽

Vadim V. Tyrenko ◽

Konstantin N. Tkachenko ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiovascular System ◽

Heart Muscle ◽

Cardiac Death ◽

Myocardial Damage ◽

Angiotensin Converting Enzyme 2 ◽

Coronary Syndrome ◽

Life Threatening ◽

Potential Benefits ◽

Myocardial Involvement

The review article is devoted to the analysis of the literature on the various mechanisms of damage to the cardiovascular system in COVID-19. The article briefly outlines the epidemiology and urgency of the COVID-19 problem, describes the features of the clinical picture of heart muscle damage in COVID-19. The pathophysiology, morphology and pathogenetic mechanisms of myocardial involvement in cases of SARS-CoV-2 lesion are considered in detail. The authors present a diagram of various mechanisms of myocardial damage in COVID-19, which includes mediated damage to the heart muscle through angiotensin-converting enzyme 2, myocardial damage caused by hypoxemia, microvascular heart damage, and systemic inflammatory response syndrome. A detailed scheme of cardiomyocyte infection with the involvement of cytokines, which ultimately leads to myocardial remodeling and dilated cardiomyopathy, is presented. The pathophysiological foundations of the development of sudden cardiac death in COVID-19, which include the mechanisms of life-threatening arrhythmias, acute coronary syndrome, and heart failure, are considered. The authors analyzed scientific studies of the toxic effects of COVID-19 drug treatment on the heart muscle, in particular, antiviral, antibacterial, antimalarial agents. Their potential benefits and harms, as well as the likelihood of developing cardiovascular events, in particular sudden cardiac death, were assessed.

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ACTIVITY OF ANGIOTENSIN-CONVERSING ENZYME-2 IN ACUTE PULMONARY INFLAMMATION

Medical Science of Ukraine (MSU) ◽

10.32345/2664-4738.3.2021.01 ◽

2021 ◽

Vol 17 (3) ◽

pp. 3-14

Author(s):

D.S. Ziablitsev ◽

O.O. Dyadyk ◽

S.V. Ziablitsev

Keyword(s):

Angiotensin Converting Enzyme ◽

Acute Inflammation ◽

Pulmonary Inflammation ◽

Renin Angiotensin System ◽

Diffuse Fibrosis ◽

Converting Enzyme ◽

Cell Infection ◽

Angiotensin Converting Enzyme 2 ◽

Coronavirus Infection ◽

Type Ii Alveolocytes

Relevance. Angiotensin converting enzyme-2 (ACE2), which is the gateway to coronavirus, is also an important component of the tissue renin-angiotensin system with a number of anti-inflammatory effects. It is known that ACE2 is expressed in the lungs of patients with coronavirus pneumonia, but it is not clear how this depends on the stages of development and the severity of inflammation. Objective: to establish the effect of acute inflammation on pulmonary expression of angiotensin-converting enzyme-2. Material and methods. In Wistar rats (n=20), in compliance with bioethical standards, a sterile nylon thread 2.5 cm long and 0.2 mm thick to a depth of 2.5 cm was introduced into the trachea. The animals were observed and removed from the experiment at 7, 14, 21 and 28 days, microscopic and immunohistochemical (monoclonal antibodies against ACE2; clone 4G5.1; EMD Millipore Corporation; Temecula, CA US) studies were performed. Results. The microscopic picture of the lungs indicated the development of acute bronchopulmonary inflammation during the first week, the formation of peribronchial and alveolar abscesses in the second week with the onset of resolution of bronchopneumonia with the organization of abscesses in the third week and the development of diffuse fibrosis of the parenchyma and vascular hyalinosis in the fourth week of observation. The exudative phase of acute inflammation was accompanied by inhibition of ACE2 activity in bronchial epithelial cells, type II alveolocytes and vascular endothelium. With the transition of inflammation to the stage of proliferation and fibrosis, ACE2 activity was restored. Conclusion. The detected phase change in ACE2 activity can cause a wavy recurrent course of coronavirus infection, since an increase in the amount of ACE2 protein during attenuation of acute inflammation contributes to an increase in target cell infection.

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Angiotensin-converting enzyme 2. Approaches to pathogenetic therapy of COVID-19

Journal of microbiology epidemiology immunobiology ◽

10.36233/0372-9311-2020-97-4-6 ◽

2020 ◽

Vol 97 (4) ◽

pp. 339-345

Author(s):

Polina O. Shatunova ◽

Anatoly S. Bykov ◽

Oksana A. Svitich ◽

Vitaly V. Zverev

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Binding Free Energy ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin Ii Receptor ◽

Angiotensin Converting Enzyme 2 ◽

Pathogenetic Therapy ◽

Receptor Blockers ◽

Coronavirus Infection

The SARS-CoV-2 virus is a pathogen causing the coronavirus infection that culminated in a worldwide pandemic in 2020. It belongs to β-coronaviruses and has high genetic similarity to the SARS-CoV virus that is responsible for an outbreak of severe acute respiratory syndrome in 2002–2003. The analysis of molecular interactions shows that SARS-CoV-2 has higher virulence due to lower binding free energy in interaction with the angiotensin-converting enzyme 2 (ACE2), which is used by the virus to enter the host cell. At the time of the global coronavirus pandemic, the thorough study of ACE2 as a key component of the disease pathogenesis comes to the fore. The detailed study of the enzyme, which is a receptor located on the surface of different tissues and which normally catalyzes the conversion of angiotensin II to angiotensin (1–7), led to diverging conclusions. Being non-tissue specific, the receptor is abundantly present in the heart, kidneys, small intestine, testes, thyroid, and adipose tissue. Besides regulating blood pressure, it suppresses inflammation, mainly in the lung tissue, participates in amino acid transport and maintains the activity of the gut microbiome. With all its essential positive functions, the role of ACE2 is highly ambiguous, specifically in coronavirus infection. The influence on the renin-angiotensin system can be seen as a promising therapeutic route in treatment of coronavirus infection. The preliminary data on using of ACE2 inhibitors, soluble forms of ACE2, and angiotensin II receptor blockers demonstrate their effectiveness and, consequently, improvement in symptoms and prognoses for patients with coronavirus infection. The review presents information about ACE2 distribution in human tissues, explores its interaction with SARS-CoV-2, provides a theoretical basis for medications involving ACE2 metabolic pathways and for using them in treatment of coronavirus infection and its prevention.

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Cardiac damage in patients with COVID-19 coronavirus infection

Arterial’naya Gipertenziya (Arterial Hypertension) ◽

10.18705/1607-419x-2020-26-3-277-287 ◽

2020 ◽

Vol 26 (3) ◽

pp. 277-287 ◽

Cited By ~ 1

Author(s):

N. G. Poteshkina ◽

M. A. Lysenko ◽

E. A. Kovalevskaya ◽

D. S. Fomina ◽

I. V. Samsonova ◽

...

Keyword(s):

Respiratory Infections ◽

Viral Myocarditis ◽

Myocardial Damage ◽

Cardiovascular Complications ◽

Cardiac Damage ◽

Coronavirus Infection ◽

Novel Coronavirus ◽

Immunohistochemical Studies ◽

Relationship Of ◽

The Relationship

The article reviews studies that confirm the relationship of a negative prognosis with the presence of risk factors for cardiovascular complications during respiratory infections, including novel coronavirus infection COVID-19. The article presents the relevant research results that provide evidence on the myocardial damage in coronavirus infection. We present a clinical case of a patient with confirmed diagnosis of COVID-19 and severe viral myocarditis, verified by histological and immunohistochemical studies.

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TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection

10.1101/2020.02.24.20025437 ◽

2020 ◽

Author(s):

Xiaoyang Ji ◽

Chunming Zhang ◽

Yubo Zhai ◽

Zhonghai Zhang ◽

Chunli Zhang ◽

...

Keyword(s):

Large Scale ◽

Renin Angiotensin System ◽

Gene Interaction ◽

Global Perspective ◽

Pathological Changes ◽

Processing Efficiency ◽

Inference System ◽

Angiotensin Converting Enzyme 2 ◽

Functional Changes ◽

Coronavirus Infection

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ACE2 as therapeutic agent

Clinical Science ◽

10.1042/cs20200570 ◽

2020 ◽

Vol 134 (19) ◽

pp. 2581-2595

Author(s):

Qiuhong Li ◽

Maria B. Grant ◽

Elaine M. Richards ◽

Mohan K. Raizada

Keyword(s):

Therapeutic Agent ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Experimental Models ◽

Electrolyte Balance ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Overwhelming Evidence ◽

Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

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