NF-κB activation during COVID-19 and its impact on patients with hypertension

By Dr. Chinta SidharthanReviewed by Benedette Cuffari, M.Sc.Oct 25 2023

In a recent study published in the journal Hypertension Research, researchers review the role of nuclear factor kappa B (NF-κB) activation in the replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the impact of coronavirus disease 2019 (COVID-19) medications on NF-κB activation.

Study: The role of SARS-CoV-2-mediated NF-κB activation in COVID-19 patients. Image Credit: Avocado_studio / Shutterstock.com

Background

SARS-CoV-2 infections exhibit substantial heterogeneity, with some infected individuals completely asymptomatic and others progressing to acute pneumonia that requires hospitalization and respiratory assistance. Severe SARS-CoV-2 infections have also resulted in various sequelae involving multiple organ systems.

However, the rapid development of various COVID-19 vaccines and subsequent global vaccination campaigns have been largely successful in reducing the spread and virulence of SARS-CoV-2. Currently, public health officials have transitioned from preventing SARS-CoV-2 infection to treating COVID-19 cases that arise following infection with new SARS-CoV-2 variants.

Various comorbidities, including hypertension, are known to increase the risk of severe COVID-19. Common hypertension medications include inhibitors of angiotensin-converting enzymes or angiotensin receptors; however, the role of the NF-κB activation, particularly the angiotensin-converting enzyme 2 (ACE2)-mediated type, in the progression of COVID-19 has not been well-studied.

About the study

In the present review, researchers examine the changes associated with NF-κB activation that occur during SARS-CoV-2 infections in the renin-angiotensin-aldosterone system (RAAS). Moreover, they discuss whether angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) used to treat hypertension can affect the severity of COVID-19.

The impact of COVID-19 medications on NF-κB activation was also assessed to elucidate how these drugs regulate the uncontrolled inflammatory responses that are characteristic of SARS-CoV-2 infections.

NF-κB activation

NF-κB is a major transcription factor that gets activated during inflammatory responses. NF-κB is typically present in its inactivated form in the cytoplasm of cells, where it is bound to the inhibitor of nuclear factor kappa B (IκB) suppressor protein.

The degradation of IκB activates NF-κB through different signaling pathways. The canonical pathway of NF-κB activation leads to further activation of other factors, such as interleukin 1 receptor, tumor necrosis factor (TNF) receptors, and toll-like receptors, resulting in inflammatory and immune responses.

The non-canonical pathway does not require the degradation of IκB. However, the phosphorylation of NF-κB inducing kinase and the receptor activator of NF-κB of B lymphocytes is essential for this process.

The abnormal activation of NF-κB has been documented in various diseases, including diabetes, immune deficiency, atherosclerosis, and inflammatory diseases.

Role of ACE-2

The ACE-2 receptor mediates the entry of SARS-CoV-2 into the host cell. In fact, the high affinity of the SARS-CoV-2 spike protein subunit 1 to the ACE-2 receptor is largely responsible for the high transmissibility of this virus.

However, ACE-2 also plays a pivotal role in the RAAS in regulating electrolyte balance and blood pressure. The binding of SARS-CoV-2 to ACE-2 could result in competitive inhibition of the catalytic activity of ACE-2, which could enhance the activation of NF-κB.

The inflammatory imbalance that results from SARS-CoV-2 infection could lead to an increased susceptibility to inflammatory cytokine storm and inflammatory imbalance in hypertension patients with COVID-19. However, previous studies have reported that treatment with ARBs and ACEIs can inhibit the activation of NF-κB and lower the secretion of pro-inflammatory cytokines in the alveolar cells in the lungs.

Treatment with ARBs and ACEIs may also reduce the number of critical cases and deaths among hypertensive COVID-19 patients. The therapeutic effects of tocilizumab, which is a monoclonal antibody treatment for COVID-19, have been enhanced when used in combination with ARBs and ACEIs in COVID-19 patients with hypertension.

COVID-19 drugs targeting NF-κB activation

Growing evidence suggests that the uncontrolled inflammatory response and cytokine storm that occurs during severe SARS-CoV-2 infection play a significant role in the development of severe post-COVID-19 sequelae. Thus, these hyper-inflammatory responses must be controlled to prevent the multi-organ dysfunction and respiratory distress that often occurs after COVID-19.

However, the administration of certain drugs used to suppress hyper-inflammatory responses, such as dexamethasone and metformin, is associated with some limitations. For example, dexamethasone has been primarily effective in patients receiving respiratory support, whereas metformin is unsuitable for patients with heart failure, renal impairments, or severe respiratory distress.

Conclusions

Treatment with ARBs and ACEIs has been shown to be beneficial in reducing the severity and mortality rates among COVID-19 patients with hypertension. Likewise, the effects of monoclonal antibody therapies have improved when combined with ARBs and ACEIs.

Further research is needed to determine the dosage, administration timings, potential contraindications, and side effects of using COVID-19 drugs that inhibit the activation of NF-κB.