scholarly journals Role of Tissue Factor in the Pathogenesis of COVID-19 and the Possible Ways to Inhibit It

2021 ◽  
Vol 27 ◽  
pp. 107602962110039
Author(s):  
Carlos A. Cañas ◽  
Felipe Cañas ◽  
Mario Bautista-Vargas ◽  
Fabio Bonilla-Abadía
Keyword(s):  
Tissue Factor ◽  
Proinflammatory Cytokines ◽  
Antiphospholipid Antibodies ◽  
Therapeutic Strategies ◽  
Prothrombotic State ◽  
Pulmonary Epithelium ◽  
Angiotensin Converting Enzyme 2 ◽  
Patients With Heart Failure ◽  
Inflammatory Effect

COVID-19 (Coronavirus Disease 2019) is a highly contagious infection and associated with high mortality rates, primarily in elderly; patients with heart failure; high blood pressure; diabetes mellitus; and those who are smokers. These conditions are associated to increase in the level of the pulmonary epithelium expression of angiotensin-converting enzyme 2 (ACE-2), which is a recognized receptor of the S protein of the causative agent SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Severe cases are manifested by parenchymal lung involvement with a significant inflammatory response and the development of microvascular thrombosis. Several factors have been involved in developing this prothrombotic state, including the inflammatory reaction itself with the participation of proinflammatory cytokines, endothelial dysfunction/endotheliitis, the presence of antiphospholipid antibodies, and possibly the tissue factor (TF) overexpression. ARS-Cov-19 ACE-2 down-regulation has been associated with an increase in angiotensin 2 (AT2). The action of proinflammatory cytokines, the increase in AT2 and the presence of antiphospholipid antibodies are known factors for TF activation and overexpression. It is very likely that the overexpression of TF in COVID-19 may be related to the pathogenesis of the disease, hence the importance of knowing the aspects related to this protein and the therapeutic strategies that can be derived. Different therapeutic strategies are being built to curb the expression of TF as a therapeutic target for various prothrombotic events; therefore, analyzing this treatment strategy for COVID-19-associated coagulopathy is rational. Medications such as celecoxib, cyclosporine or colchicine can impact on COVID-19, in addition to its anti-inflammatory effect, through inhibition of TF.

Effect of miRNAs, proinflammatory cytokines and ACE2 in COVID-19 pathophysiology

Coronaviruses ◽  
2021 ◽  
Vol 02 ◽  
Author(s):  
Hari Om Singh ◽  
Kamini Jakhar ◽  
Vijay Nema ◽  
Asha Krishnaraj ◽  
Ranjana Choudhari
Keyword(s):  
Proinflammatory Cytokines ◽  
Target Genes ◽  
Rapid Identification ◽  
Host Factors ◽  
Angiotensin Converting Enzyme 2 ◽  
Proinflammatory Mediator ◽  
Proinflammatory Mediators ◽  
Heart Blood ◽  
The Difference

Background: Angiotensin converting enzyme 2 (ACE2) is the main cellular receptor for entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and acts as a proinflammatory mediator of Coronavirus disease (COVID-19). The clinical outcome of SARS-CoV-2 infection is influenced by proinflammatory mediators. The specific microRNAs (miRNAs) influence the ACE2 expression and are accountable for the increased circulatory proinflammatory mediator levels. Thus host factors play a crucial role in COVID-19 pathophysiology. The pathogenesis of COVID-19 disease is not well understood. Hence we comprehended the role of miRNAs, proinflammatory cytokines and ACE2 in COVID-19 pathophysiology. Methods: We utilized multiple databases, specifically, EMBASE, PubMed (Medline) and Google Scholar for our search. Discussion: SARS-CoV-2 genes could be target of host miRNAs. The miRNAs regulate the expression of ACE2 in various organs including kidney, heart, blood vessels, and lung. ACE2 acts as a proinflammatory mediator of SARS-CoV-2 associated disease. Proinflammatory cytokines (IL-6, IL-1β and TNF) have been associated with severe COVID-19 disease. Hence variation in expression of miRNAs would influence the regulation of COVID-19 pathophysiology. The clinical outcomes of COVID -19 are variable which could be linked with the difference in binding of host miRNA to target genes. Conclusion: Correlation of these genes with severe or critical stages of patients will provide biomarkers for severity of lung inflammation which would be useful in rapid identification of patients in need of hospital admission. Analysis of relationship between the miRNAs and ACE2 will be helpful in designing anti-miR therapy for ACE2-related SARS-CoV-2 infection.

Pathophysiology of β2-glycoprotein I in antiphospholipid syndrome

Lupus ◽  
2010 ◽  
Vol 19 (4) ◽  
pp. 379-384 ◽  
Author(s):  
E. Matsuura ◽  
L. Shen ◽  
Y. Matsunami ◽  
N. Quan ◽  
M. Makarova ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Antiphospholipid Syndrome ◽  
Mechanism Of Action ◽  
Antiphospholipid Antibodies ◽  
Physiological Role ◽  
Therapeutic Strategies ◽  
Physiological Functions ◽  
Glycoprotein I ◽  
The Impact

Since β2-glycoprotein I (β2GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of β2GPI and anti-β2GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of β2GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. β2GPI’s epitopes for anti-β2GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-β2GPI antibodies are pathogenic. The pathophysiologic role of β2GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of β2GPI, its metabolites and autoantibodies to β2GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease. Lupus (2010) 19, 379—384.

scholarly journals Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

2020 ◽  
Vol 11 ◽  
Author(s):  
Nabab Khan ◽  
Xuesong Chen ◽  
Jonathan D. Geiger
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Rna Virus ◽  
Therapeutic Strategies ◽  
Host Protein ◽  
Focus Attention ◽  
Angiotensin Converting Enzyme 2 ◽  
Immunological Responses ◽  
Endocytic Machinery ◽  
Replication Sites

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an enveloped, single-stranded RNA virus. Humans infected with SARS-CoV-2 develop a disease known as coronavirus disease 2019 (COVID-19) with symptoms and consequences including acute respiratory distress syndrome (ARDS), cardiovascular disorders, and death. SARS-CoV-2 appears to infect cells by first binding viral spike proteins with host protein angiotensin-converting enzyme 2 (ACE2) receptors; the virus is endocytosed following priming by transmembrane protease serine 2 (TMPRSS2). The process of virus entry into endosomes and its release from endolysosomes are key features of enveloped viruses. Thus, it is important to focus attention on the role of endolysosomes in SARS-CoV-2 infection. Indeed, coronaviruses are now known to hijack endocytic machinery to enter cells such that they can deliver their genome at replication sites without initiating host detection and immunological responses. Hence, endolysosomes might be good targets for developing therapeutic strategies against coronaviruses. Here, we focus attention on the involvement of endolysosomes in SARS-CoV-2 infection and COVID-19 pathogenesis. Further, we explore endolysosome-based therapeutic strategies to restrict SARS-CoV-2 infection and COVID-19 pathogenesis.

scholarly journals New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Anderson J. Ferreira ◽  
Tatiane M. Murça ◽  
Rodrigo A. Fraga-Silva ◽  
Carlos Henrique Castro ◽  
Mohan K. Raizada ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Therapeutic Strategies ◽  
Biologically Active ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
G Protein Coupled ◽  
Hydrolysis Of

Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1–7). The axis formed by ACE2/Ang-(1–7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT1receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis.

It Takes Two to Tango: Secondary Entry Pathway for SARS-CoV-2 Induces Analgesia

2021 ◽  
Author(s):  
R. Weill Rossi
Keyword(s):  
Viral Entry ◽  
Therapeutic Strategies ◽  
Mechanisms Of Action ◽  
Vascular Endothelial ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Pathway ◽  
Neuropilin 1 ◽  
New Compounds ◽  
Endothelial Growth Factor

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to impact the world, its mechanisms of action begin to unravel. The main entry pathway for SARS-CoV-2 into the cell is thought to be through binding to the angiotensin converting enzyme 2, but it seems another protein can induce its viral entry: neuropilin-1 receptor (NRP-1). NRP-1 is usually bound by vascular endothelial growth factor-A (VEGF-A), a - amongst other- pronociceptive factor. By binding to NRP-1, the Spike protein of SARS-CoV-2 blocks neuronal signaling, reducing the pro-nociceptive implication of VEGF-A. This analgesic role of SARS-CoV-2 gave rise to an increase in screenings for new compounds that could interfere with this pathway. Preventing VEGFA from binding to NRP1 opens new possibilities for therapeutic strategies in the field of neuropathic pain.

scholarly journals SARS-CoV-2 infection induces the activation of tissue factor-mediated coagulation by activation of acid sphingomyelinase

Blood ◽  
2021 ◽  
Author(s):  
Jue Wang ◽  
Usha R. Pendurthi ◽  
Guohua Yi ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Tissue Factor ◽  
Human Monocyte ◽  
Acid Sphingomyelinase ◽  
Procoagulant Activity ◽  
Angiotensin Converting Enzyme 2 ◽  
Phosphatidylserine Externalization ◽  
Activity Inhibition ◽  
Outer Leaflet ◽  
Hydrolysis Of

SARS-CoV-2 infection is associated with the hypercoagulable state. Tissue factor (TF) is the primary cellular initiator of coagulation. Most of the TF expressed on cell surfaces remains cryptic. Sphingomyelin (SM) is responsible for maintaining TF in the encrypted state, and hydrolysis of SM by acid sphingomyelinase (ASMase) increases TF activity. ASMase was shown to play a role in virus infection biology. In the present study, we investigated the role of ASMase in SARS-CoV-2 infection-induced TF procoagulant activity. Infection of human monocyte-derived macrophages (MDMs) with SARs-CoV-2 spike protein pseudovirus (SARS-CoV-2-SP-PV) markedly increased TF procoagulant activity at the cell surface and released TF+ extracellular vesicles (EVs). The pseudovirus infection did not increase either TF protein expression or phosphatidylserine externalization. SARS-CoV-2-SP-PV infection induced the translocation of ASMase to the outer leaflet of the plasma membrane, which led to the hydrolysis of SM in the membrane. Pharmacological inhibitors or genetic silencing of ASMase attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Inhibition of SARS-CoV-2 receptor, angiotensin-converting enzyme-2, attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Overall, our data suggest that SARS-CoV-2 infection activates the coagulation by decrypting TF through activation of ASMase. Our data suggest that the FDA-approved functional inhibitors of ASMase may help treat hypercoagulability in COVID-19 patients.

Factor Xa Enhances the Binding of Tissue Factor Pathway Inhibitor to Acidic Phospholipids

1996 ◽  
Vol 75 (05) ◽  
pp. 796-800 ◽  
Author(s):  
Sanne Valentin ◽  
Inger Schousboe
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Factor Xa ◽  
Microtitre Plate ◽  
C Terminus ◽  
Microtitre Plate Assay ◽  
Kunitz Domain ◽  
Tissue Factor Pathway ◽  
Acidic Phospholipids

SummaryIn the present study, the interaction between tissue factor pathway inhibitor (TFPI) and phospholipids has been characterized using a microtitre plate assay. TFPI was shown to bind calcium-independently to an acidic phospholipid surface composed of phosphatidylserine, but not a surface composed of the neutral phosphatidylcholine. The interaction was demonstrated to be dependent on the presence of the TFPI C-terminus. The presence of heparin (1 U/ml, unfractionated) was able to significantly reduce the binding of TFPI to phospholipid. The interaction of TFPI with phosphatidylserine was significantly decreased in the presence of calcium, but this was counteracted, and even enhanced, following complex formation of TFPI with factor Xa prior to incubation with the phospholipid surface. Moreover, a TFPI variant, not containing the third Kunitz domain and the C-terminus, was unable to bind to phospholipid. However, following the formation of a TFPI/factor Xa-complex this TFPI variant was capable of interacting with the phospholipid surface. This indicates that the role of factor Xa as a TFPI cofactor, at least in part, is to mediate the binding of TFPI to the phospholipid surface.

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