ACE2-Mediated Endothelial Inflammation in COVID-19

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially recognized as a respiratory infection, has evolved into a complex systemic disease with a range of cardiovascular complications.

These complications encompass thrombosis, hypertension, myocarditis, heart failure, arrhythmias, and acute kidney injury.

The link between COVID-19 and cardiovascular comorbidities is intricately related to the multifaceted role of angiotensin-converting enzyme 2 (ACE2).

ACE2 is a key enzyme in the renin-angiotensin-aldosterone system (RAAS), maintaining vascular balance by degrading the vasoconstrictor Angiotensin II (Ang II) and generating the vasodilator Angiotensin-(1-7) [Ang(1-7)].

The connection between ACE2 and COVID-19-associated cardiovascular complications remains elusive, prompting further investigation into the mechanisms underlying endothelial dysfunction and inflammation.

The Pleiotropic Role of ACE2 in Cardiovascular Complications

ACE2 has garnered attention not only as the entry receptor for SARS-CoV-2 but also for its implications in cardiovascular health. COVID-19-associated tissue damage extends beyond the respiratory system, involving immune pathway activation that adversely affects vascular cells, particularly endothelial cells. This cascade of events culminates in the loss of endothelial integrity, vascular dysfunction, and inflammation, collectively referred to as endotheliitis. The precise molecular mechanisms underlying endotheliitis in COVID-19 are under continuous scrutiny.

SARS-CoV-2 Spike Protein and Endothelial Inflammation

Recent studies have unearthed a pivotal role of the SARS-CoV-2 spike protein (S protein) in inducing endothelial inflammation. It has been revealed that SARS-CoV-2 triggers the production of pro-inflammatory molecules, including cytokines (IL-6, TNFα), chemokines (MCP-1), PAI-1, and adhesion molecules (ICAM-1, VCAM-1), subsequently activating pro-inflammatory signaling pathways like NFκB and ERK1/2 in endothelial cells. These molecular events are associated with the formation of microparticles, indicative of endothelial cell damage and apoptosis, as well as cellular activation and proliferation.

Clinical Correlations and Inflammatory Cytokines

Clinical investigations underscore the significance of raised serum levels of IL-6 and TNF-α as prognostic indicators in COVID-19 patients. These cytokines, pivotal in STAT3 activation and PAI-1 expression, contribute to the hypercoagulable state associated with COVID-19. The findings of these clinical studies align seamlessly with the in vitro observations, further highlighting the involvement of endothelial ACE2 in modulating these inflammatory responses.

ACE2 as a Non-Catalytic Signaling Protein

Beyond its enzymatic role in RAAS, ACE2 emerges as a non-catalytic signaling protein. This novel perspective is supported by experiments demonstrating that ACE2 inhibition curtails S protein-induced inflammation without altering ACE2 enzymatic activity. Intriguingly, ACE2’s involvement in inflammatory processes isn’t limited to COVID-19; it has been linked to atherosclerosis and heart disease. Co-immunoprecipitation proteomics studies underline ACE2’s interaction with several pro-inflammatory signaling molecules in endothelial cells treated with the S protein.

Diverse Mechanisms of Inflammation

While ACE2 plays a central role, it is important to consider the multifaceted mechanisms contributing to S protein-induced inflammation.

In addition to ACE2, other receptors, such as glucose-regulated protein 78 (GRP78), have been implicated as receptors for the S protein. GRP78 translocates under cellular stress, potentially initiating a cascade of events leading to cytokine production, similar to the danger-associated molecular pattern (DAMP) mechanism.

Toll-like receptor (TLR) activation could also contribute to the inflammatory response induced by the S protein.

Conclusion

In summary, the investigation into the interplay between ACE2 and the SARS-CoV-2 spike protein has unveiled a critical role for ACE2 in orchestrating pro-inflammatory signaling and endothelial inflammation. Notably, this action of ACE2 occurs independent of its enzymatic activity and viral replication.

These findings offer fresh insights into the intricate cardiovascular complications of COVID-19, particularly endotheliitis, and underscore ACE2 as a potential therapeutic target in managing COVID-19-associated cardiovascular issues. It is essential to acknowledge that this research was conducted with the initial SARS-CoV-2 strain, and the evolving viral mutations might influence the inflammatory responses in various ways, warranting further exploration.

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reference link : https://www.nature.com/articles/s41598-023-41115-3