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Source: Medical News -SARS-CoV-2 Disrupts Endothelial Barrier  Sep 28, 2022  2 years, 2 weeks, 1 day, 13 hours, 24 minutes ago

Japanese Study Finds That SARS-CoV-2 From Infected Epithelial Cells Disrupts The Endothelial Barrier By Downregulating Claudin-5 (CLDN5), A Tight Junction Protein

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Japanese Study Finds That SARS-CoV-2 From Infected Epithelial Cells Disrupts The Endothelial Barrier By Downregulating Claudin-5 (CLDN5), A Tight Junction Protein
Source: Medical News -SARS-CoV-2 Disrupts Endothelial Barrier  Sep 28, 2022  2 years, 2 weeks, 1 day, 13 hours, 24 minutes ago
A new study by researchers from Kyoto University-Japan and Osaka University-Japan has found the detailed mechanism by which SARS-CoV-2 invades into the blood vessels.


 
It was found that SARS-CoV-2 from infected epithelial cells disrupts the endothelial barrier by downregulating Claudin-5 (CLDN5), a tight junction protein.
 
CLDN5 (Claudin 5) is a protein coding gene that contains 218 amino acids and  is part of the claudin family consisting of 24 known transmembrane proteins exhibiting distinct tissue- and development-specific distribution patterns. They are detected in both epithelial and endothelial cells and form a complex with occludin and/or JAMs.
 
It should be noted that diseases associated with CLDN5 include Velocardiofacial Syndrome and Brain Edema. Among its related pathways are the Blood-Brain Barrier and Immune Cell Transmigration ie the VCAM-1/CD106 Signaling and Integrin Pathway.
 
It is already known that in the initial process of COVID-19 disease, the SARS-CoV-2 coronavirus infects respiratory epithelial cells and then transfers to other organs the blood vessels.
 
It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism.
 
The study team investigated the effect of SARS-CoV-2 on the endothelial barrier utilizing an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin–mediated adherens junctions.
 
Consistently, the gene and protein expression levels of CLDN5 in the lungs of a patient with COVID-19 were decreased. CLDN5 overexpression or Fluvastatin treatment rescued the SARS-CoV-2–induced respiratory endothelial barrier disruption.
 
The study findings shows that the down-regulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2–induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a therapeutic strategy against COVID-19.
 
The study findings were published in the peer reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.abo6783
 
The study was led by CiRA Junior Associate Professor Dr Kazuo Takayama and Associate Professor Dr Yoshiaki Okada of Osaka University.
 
This is the first study to explain in detail how the SARS-CoV-2 virus disrupts the vascular endothelial barrier by suppressing the expression of Claudin-5 (CLDN5) to invade the blood vessels.
 
It was already known or a long time that the SARS-CoV-2 virus is able to cross the walls of blood vessels (the barrier of vascular endothelial cells) from respiratory organs and enters the blood vessels. However, the detailed mechanism was unknown.
 
The study team created an airway-on-a-chip that mimics respiratory organs consisting of airway epithelial cells and vascular endothelial cells.
 
Utilizing the device, the study team found that SARS-CoV-2 disrupts the vascular endothelial barrier by suppressing the expression of CLDN5, a protein involved in adhesive junctions between vascular endothelial cells, and by subsequent ly weakening the vascular endothelial cadherin-mediated junctions.
 
The study team confirmed that CLDN5 gene and protein expression levels were decreased in the lungs of a patient with COVID-19.
 
Dr Takayama told Thailand Medical News, “Our study findings demonstrated that increasing CLDN5 expression in vascular endothelial cells by gene transfer or small molecule drugs (fluvastatin) suppressed SARS-CoV-2-induced vascular endothelial barrier disruption.”
 
Fluvastatin is a member of the statin drug class used to treat high levels of cholesterol in the blood or hypercholesterolemia and to prevent cardiovascular disease. It is sold under the brandname Lescol XL.
 
The study findings indicate that suppression of CLDN5 expression is an essential mechanism for SARS-CoV-2-induced vascular endothelial barrier disruption, which increases the severity of COVID-19.
 
The study findings also indicate that up-regulation of CLDN5 expression is a new therapeutic strategy against COVID-19.
 
The novel airway-on-a-chip technology, which can be used to reproduce the respiratory pathology of COVID-19 and search for therapeutic agents, is expected to become an excellent tool for elucidating the pathogenesis of severe respiratory tract infections, including COVID-19, and developing therapeutic drugs in the future.
 
For the latest SARS-CoV-2 Research, keep on logging to Thailand Medical News.
 

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