American Study Finds That SARS-CoV-2 Nsp6, Nsp8 And M Proteins Damage Human Cardiomyocytes By Reducing ATP Levels!

COVID-19 News: The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has shaken the world since its emergence in late 2019. While respiratory complications have been at the forefront of the clinical manifestations, it's becoming increasingly clear that the virus can also wreak havoc on the cardiovascular system, with dire consequences for patients.


 
Cardiovascular complications, including acute myocardial injury, myocarditis, arrhythmias, and sudden death, have been identified as significant contributors to COVID-19-related mortality as seen in various past case reports, studies and COVID-19 News coverages. In fact, a substantial percentage of COVID-19 patients develop concurrent cardiovascular disorders, and individuals with pre-existing cardiovascular conditions face a notably higher mortality rate.
 
As the pandemic rages on, researchers are diligently working to understand how SARS-CoV-2 impacts the heart. Recent studies have shed light on the virus's ability to directly infect cardiomyocytes, the cells responsible for the heart's contractile function. This revelation has raised important questions about the specific viral genes responsible for these detrimental effects on cardiomyocytes and potential therapeutic strategies to counteract them.
 
This new study conducted by the Indiana University School of Medicine, USA, which uncovers the damaging effects of three SARS-CoV-2 genes, namely Nsp6, Nsp8, and M, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). This research not only elucidates the molecular mechanisms behind the harm caused by these viral proteins but also highlights promising therapeutic avenues for mitigating their effects on heart health.
 
Understanding the Vulnerability of Cardiomyocytes
Cardiovascular complications in COVID-19 patients are a pressing concern, and understanding their underlying mechanisms is crucial for effective management. To address this, the study team turned their attention to hPSC-CMs, a model system that allows them to investigate the impact of SARS-CoV-2 genes on human heart muscle cells.

SARS-CoV-2 enters human cells by binding to specific membrane proteins, including Angiotensin-Converting Enzyme 2 (ACE2). Given the high expression of ACE2 in the heart, cardiomyocytes are prime targets for the virus. Previous studies using hPSC-CMs have revealed that SARS-CoV-2 infection leads to increased cell death, disrupted sarcomeres (the contractile units of muscle cells), abnormal electrical and mechanical functions, and inflammation. These findings mirror the cardiac injuries observed in COVID-19 patients, further emphasizing the need to understand the molecular mechanisms at play.
 
Deciphering the Role of SARS-CoV-2 Genes
The SARS-CoV-2 genome encodes a total of 27 genes, but their individual impacts on host cardiomyocytes remained a mystery. This study set out to investigate the specific effects of three viral genes: Nsp6, Nsp8, and M, on hPSC-CMs.
Nsp6 and Nsp8 are non-structural proteins, while M is the most abundant structural protein in the SARS-CoV-2 virus. To understand the consequences of overexpressing the se genes in hPSC-CMs, the researchers employed cutting-edge techniques, including whole mRNA-seq and mass spectrometry for multi-omics analysis. This allowed them to comprehensively examine how these viral genes alter the transcriptome and proteome of cardiomyocytes.
 
The findings were striking. Overexpression of Nsp6, Nsp8, or M in hPSC-CMs led to the activation of genes associated with cellular injury and immune signaling pathways, while simultaneously suppressing genes linked to cardiac function. This observation suggests that these viral proteins have a profound impact on the genetic makeup of cardiomyocytes, pushing them towards a state of dysfunction and inflammation.
 
A Cascade of Cellular Consequences
The repercussions of SARS-CoV-2 genes didn't stop at altering gene expression patterns. Overexpression of Nsp6, Nsp8, or M in hPSC-CMs had dire consequences for cell health and function. It significantly increased apoptosis (programmed cell death) and compromised the handling of calcium ions, which is critical for cardiac contractility.
 
Importantly, the researchers discovered a direct interaction between these viral proteins and ATPase subunits, namely ATP5A1 and ATP5B. This interaction disrupted the production of adenosine triphosphate (ATP), the cell's energy currency. Cellular ATP levels play a pivotal role in maintaining cardiomyocyte viability and contractility, making this discovery particularly significant.
 
Restoring Cellular Energy: A Promising Therapeutic Approach
Recognizing the central role of ATP depletion in the harm caused by Nsp6, Nsp8, and M, the researchers explored potential pharmaceutical interventions to enhance ATP levels and mitigate the resulting cell death and dysfunction in hPSC-CMs.
 
Their investigation led to the identification of two FDA-approved drugs, ivermectin and meclizine, as potential candidates. Ivermectin, traditionally used for parasitic infections, was found to protect mitochondrial ATP levels in cardiomyocytes. It achieved this by upregulating the transcription of Cox6a2, a subunit of the mitochondrial respiratory chain, thereby boosting ATP production. Meclizine, on the other hand, had cardio-protective effects by promoting glycolysis in cardiomyocytes, which increased ATP synthesis and preserved mitochondrial function.
 
These findings suggest that ivermectin and meclizine may hold promise as therapeutic agents to counteract the detrimental effects of SARS-CoV-2 genes on cardiomyocytes. By enhancing cellular ATP levels, these drugs could potentially reduce cell death and improve cardiac function in COVID-19 patients.
 
Conclusion
The COVID-19 pandemic continues to pose a significant threat to global health, with cardiovascular complications playing a substantial role in patient morbidity and mortality. This study conducted by the Indiana University School of Medicine sheds light on the damaging effects of SARS-CoV-2 genes Nsp6, Nsp8, and M on human pluripotent stem cell-derived cardiomyocytes.
 
The research not only uncovers the molecular mechanisms behind the harm caused by these viral proteins but also highlights the potential of FDA-approved drugs, ivermectin and meclizine, in mitigating these effects. By enhancing cellular ATP levels, these drugs offer a promising avenue for protecting cardiac function in COVID-19 patients, potentially reducing the burden of cardiovascular complications associated with the disease.
 
As the world continues to grapple with the ongoing pandemic, studies like this one bring us one step closer to understanding the intricacies of the virus's impact on the human body and identifying effective treatments to combat its devastating effects on the heart.
 
The study findings were published in the peer reviewed journal: Stem Cell Research And Therapy.
https://stemcellres.biomedcentral.com/articles/10.1186/s13287-023-03485-3
 
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