Deciphering the Molecular Impact of SARS-CoV-2 Genes Nsp6, Nsp8, and M on Human Cardiomyocytes and Potential Therapeutic Strategies

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Since its emergence in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has left an indelible mark on global public health.

With over 760 million confirmed cases worldwide and a staggering death toll exceeding 1,112,000 in the USA alone, the virus has posed an unprecedented challenge [1,2].

While respiratory failure is the primary cause of death in COVID-19 patients, cardiac complications such as acute myocardial injury, myocarditis, arrhythmias, and sudden death have significantly contributed to overall mortality [3,4,5].

Remarkably, 8–25% of SARS-CoV-2 patients develop concurrent cardiovascular disorders, and these conditions are especially prevalent among COVID-19-related fatalities [6]. Furthermore, individuals with pre-existing cardiovascular conditions exhibit a higher mortality rate when infected with the virus [7,8].

Disturbingly, recent studies have unveiled persistent cardiovascular risks, including inflammatory myocarditis, right ventricular injury, ventricular arrhythmias, myocardial infarction, and heart failure, even up to 12 months post-infection [9,10].

This article delves into the molecular intricacies of how specific SARS-CoV-2 genes, Nsp6, Nsp8, and M, impact human cardiomyocytes (CMs) and explores potential therapeutic interventions.

The SARS-CoV-2 Viral Genome and Its Interaction with Human Cells

The SARS-CoV-2 genome encompasses up to 27 genes, among which Nsp6, Nsp8, and M have been shown to have notable effects on human cells. These genes have been implicated in apoptosis induction and dysfunction in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) [21].

To understand the full extent of their impact, comparative analyses of transcriptomic changes induced by SARS-CoV-2 infection and overexpression of these genes in hPSC-CMs have been conducted. These analyses revealed that these genes can activate pathways associated with cellular injury and immune signaling while concurrently suppressing genes linked to cardiac functionality [21].

Direct Effects on Human Cardiomyocytes

Overexpression of Nsp6, Nsp8, and M in hPSC-CMs has been shown to lead to increased apoptosis and compromised calcium handling, resembling the CM injuries observed in COVID-19 patients [11,21].

The interaction of these viral genes with key ATPase subunits, particularly ATP5A1 and ATP5B, has been identified as a significant factor in the observed effects. This interaction results in a noticeable reduction in cellular ATP levels, which plays a pivotal role in CM death and abnormalities induced by these SARS-CoV-2 genes [21].

Pharmaceutical Strategies to Enhance ATP Levels

Given the critical role of ATP in maintaining CM viability and contractility, pharmaceutical interventions to enhance cellular ATP levels in hPSC-CMs overexpressing Nsp6, Nsp8, or M have been explored. Two FDA-approved drugs, ivermectin and meclizine, have shown promise in this regard.

Ivermectin, primarily used to treat parasitic infections, has been identified as a mitochondrial ATP protector in CMs, enhancing mitochondrial ATP production and, consequently, cellular ATP levels [41]. Meclizine, on the other hand, exhibits cardio-protective effects by promoting CMs’ glycolysis, increasing ATP synthesis, mitigating ATP depletion, and protecting mitochondrial function [43,54].

These findings suggest that these drugs could serve as therapeutic options to mitigate the deleterious effects of SARS-CoV-2 genes on hPSC-CMs.

Discussion

Cardiac manifestations resulting from SARS-CoV-2 infection are of paramount concern for both acute and post-acute COVID-19 patients [9,49,50]. This study sheds light on the genome-wide repercussions of specific SARS-CoV-2 genes, namely Nsp6, Nsp8, and M, on human pluripotent stem cell-derived cardiomyocytes, offering critical insights into the molecular pathogenesis of COVID-19-related cardiac dysfunction.

Additionally, the study demonstrates that FDA-approved drugs such as ivermectin and meclizine can enhance cellular ATP levels, subsequently ameliorating apoptosis and functional abnormalities induced by these genes in hPSC-CMs.

In summary, this research provides valuable insights into the detrimental effects of select SARS-CoV-2 genes on the survival and function of human cardiomyocytes, as well as potential therapeutic interventions to protect cardiac function in COVID-19 patients.

Conclusion

SARS-CoV-2 infection poses a persistent risk of cardiovascular diseases, even one year post-infection, regardless of patient age or gender. This study highlights the susceptibility of human pluripotent stem cell-derived cardiomyocytes to three specific SARS-CoV-2 genes: Nsp6, Nsp8, and M.

These genes induce apoptosis and dysfunction in cardiomyocytes, suggesting their potential detrimental impacts on other SARS-CoV-2 target organs and tissues.

Notably, these genes interact with ATPase subunits, leading to a reduction in ATP levels, which is central to the cell death and functional abnormalities observed. The study also identifies FDA-approved drugs that can enhance cellular ATP levels, offering a potential therapeutic strategy to address COVID-19-induced cardiac injuries and functional abnormalities. This research contributes significantly to our understanding of the molecular mechanisms underlying COVID-19-related cardiac complications and provides a foundation for potential therapeutic interventions.


reference link:https://stemcellres.biomedcentral.com/articles/10.1186/s13287-023-03485-3#Sec27

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