Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

Area of Science:

• Cardiovascular Biology
• Infectious Disease Pathophysiology
• Pharmacology

Background:

• The renin-angiotensin system (RAS) plays a critical role in cardiovascular homeostasis.
• Severe COVID-19 is associated with complex pathophysiological changes potentially involving RAS dysregulation.
• ACE2 (Angiotensin-Converting Enzyme 2) is a key component of the RAS, known to be targeted by SARS-CoV-2.

Purpose of the Study:

• To elucidate the pathophysiological role of the renin-angiotensin system (RAS) in COVID-19 progression.
• To investigate the proposed hypothesis of early ACE2 upregulation followed by late-phase RAS hyperactivity in COVID-19.
• To propose phase-specific pharmacological inhibition of RAS enzymes as a therapeutic strategy.

Main Methods:

• Review and synthesis of existing evidence on SARS-CoV-2 interaction with the RAS.
• Analysis of the proposed dual-phase mechanism involving ACE2, ADAM17, and downstream RAS components.
• Hypothesizing therapeutic interventions targeting specific RAS enzymes based on disease phase.

Main Results:

• SARS-CoV-2 initially upregulates ACE2 activity, increasing protective peptides (Ang 1-7, Ang 1-9).
• Severe COVID-19 involves a late phase of compensatory RAS activation (renin, ACE), leading to inflammation, hypertension, and thrombosis.
• This hyperactivity creates positive feedback loops sustaining RAS activation, potentially causing Long-COVID.

Conclusions:

• The renin-angiotensin system (RAS) is central to COVID-19 pathogenesis, exhibiting distinct early and late phases.
• Phase-specific inhibition of RAS enzymes offers a potential therapeutic strategy to prevent disease progression and adverse effects.
• Targeting these feedback loops may mitigate severe COVID-19, vaccine-induced complications, and Long-COVID syndrome.