The COVID-19 pandemic has posed significant challenges, particularly for individuals with pre-existing conditions like hypertension. A recent study explored the effects of two common antihypertensive medications, losartan and enalapril maleate, on SARS-CoV-2 infection in Vero cells. The findings revealed that losartan substantially reduced the levels of SARS-CoV-2 nucleocapsid RNA, while enalapril maleate did not show a significant effect. Interestingly, the treatments also influenced the expression of genes involved in cell cycle regulation, inflammation, and autophagy, suggesting that these drugs could interfere with the cellular processes hijacked by the virus. Understanding these complex interactions is crucial for unraveling how antihypertensive medications might impact the course of COVID-19 in patients.
Unraveling the Role of Antihypertensive Drugs in SARS-CoV-2 Infection
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has posed significant challenges to global healthcare systems. Individuals with pre-existing conditions, such as hypertension, are particularly at risk of developing severe complications from the infection. This has raised concerns about the safety and potential impact of commonly prescribed antihypertensive medications, such as angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEis), on COVID-19 outcomes.
Exploring the Differential Effects of Losartan and Enalapril Maleate
A recent study, published in the journal Scientific Reports, delved into the influence of two antihypertensive drugs, losartan and enalapril maleate, on SARS-CoV-2 infection in Vero E6 cells, a common model for studying the virus. The researchers aimed to assess the impact of these medications on viral replication, cell viability, and the expression of key cellular genes.
Assessing the Antiviral Activity and Cell Viability
The study first evaluated the cytotoxicity of losartan and enalapril maleate on Vero E6 cells, and the results showed that both compounds were non-toxic, even at the highest concentrations tested. When the cells were infected with SARS-CoV-2, the researchers observed a significant reduction in cell viability compared to uninfected cells. Interestingly, the addition of losartan at higher concentrations (500 μM and 1000 μM) improved the cell viability of infected cultures, suggesting a potential antiviral effect. In contrast, enalapril maleate treatment did not demonstrate a comparable improvement in cell viability.
Fig. 2
Targeting Viral Replication and the ACE2 Receptor
To further investigate the antiviral activity, the researchers quantified the levels of SARS-CoV-2 nucleocapsid RNA, a marker of viral replication. Their findings revealed that losartan at the highest concentration (1000 μM) substantially attenuated the levels of viral RNA, while enalapril maleate did not show a significant effect.
The study also examined the expression of the ACE2 gene, which encodes the primary receptor used by SARS-CoV-2 to gain entry into host cells. Interestingly, both losartan and enalapril maleate treatments reduced the levels of ACE2 mRNA in infected cells compared to the infected-untreated group, suggesting a potential mechanism by which these drugs could interfere with viral entry.
Modulating Cellular Pathways: Inflammation, Cell Cycle, and Autophagy
The researchers further investigated the impact of the treatments on the expression of several genes involved in key cellular processes, such as inflammation, cell cycle regulation, and autophagy.
Fig. 3
Regarding inflammation, the study found that SARS-CoV-2 infection led to an upregulation of the IL-6 and IL-18 genes, which encode pro-inflammatory cytokines. Interestingly, both losartan and enalapril maleate treatments increased the expression of IL-6 in infected cells, suggesting that the protective effects of these drugs may not be directly related to their anti-inflammatory properties.
In terms of cell cycle regulation, the researchers observed that SARS-CoV-2 infection increased the expression of the p53, p21, and p62 genes, which play crucial roles in cell cycle arrest, DNA repair, and autophagy, respectively. Notably, the 1000 μM losartan treatment was able to reduce the expression of p21 in infected cells, potentially indicating a mechanism by which this drug could inhibit viral replication.
Fig. 4
Regarding autophagy, the study found that SARS-CoV-2 infection upregulated the expression of p62, a key regulator of this cellular process. Both losartan and enalapril maleate treatments were able to reduce the levels of p62 mRNA in infected cells, suggesting that they may influence the virus’s ability to hijack the autophagy machinery for its own replication and survival.
Unraveling the Complexity of Antihypertensive Drugs and COVID-19
The findings from this study highlight the intricate relationship between antihypertensive medications and SARS-CoV-2 infection. While both losartan and enalapril maleate were able to modulate the expression of genes involved in key cellular pathways, their influence on viral replication and cell viability differed significantly.
The data suggest that losartan may have a more direct antiviral effect, potentially by inhibiting viral entry and replication, while enalapril maleate’s influence appears to be more complex, affecting various signaling cascades without a significant impact on viral RNA levels.
These insights underscore the importance of understanding the nuanced interactions between antihypertensive drugs and SARS-CoV-2, as they may have implications for the management and prognosis of COVID-19 patients with pre-existing hypertension. Further research is needed to elucidate the precise mechanisms underlying these differential effects and to explore the potential clinical applications of these findings.
Author credit: This article is based on research by Julia H. Majolo, João I. B. Gonçalves, Renata P. Souza, Laura C. González, Nathalia Sperotto, Maiele D. Silveira, Sílvia D. Oliveira, Cristiano V. Bizarro, Pablo Machado, Luiz A. Basso, Ana P. D. Souza, Jarbas R. Oliveira, Carlos A. S. Ferreira.
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