Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

Area of Science:

• Cardiovascular Pharmacology
• Infectious Disease Research
• Respiratory Medicine

Background:

• The renin-angiotensin system (RAS) plays a dual role in COVID-19 pathogenesis via angiotensin-converting enzyme 2 (ACE2).
• ACE2 is crucial for tissue inflammation control but also serves as the viral entry receptor.
• Controversy exists regarding RAS-modulating drugs, commonly used by vulnerable populations, and their impact on ACE2 and COVID-19 severity.

Purpose of the Study:

• To investigate the effect of candesartan (ARB) and captopril (ACEI) on ACE2 expression and the anti-inflammatory RAS axis in lung tissue.
• To determine if these drugs influence ACE2 expression and response to viral spike protein in human pneumocytes.

Main Methods:

• Administration of candesartan and captopril to healthy and metabolically compromised rats.
• Treatment of human type-II pneumocyte cultures with drugs and viral spike protein.
• Measurement of ACE2 expression, ADAM17 activity, inflammatory cytokines, and viral protein internalization.

Main Results:

• Candesartan and captopril up-regulated ACE2 and anti-inflammatory RAS receptors (AT2, Mas) in rat lungs, particularly in aged and metabolically affected rats.
• These drugs increased ACE2 expression in human pneumocytes.
• Viral spike protein decreased full-length ACE2, increased soluble ACE2, and elevated ADAM17 activity and pro-inflammatory cytokines; pretreatment with drugs counteracted these effects and reduced viral entry.

Conclusions:

• Candesartan and captopril enhance ACE2 levels and promote the anti-inflammatory RAS axis in the lungs.
• Drug-induced increase in transmembrane ACE2 expression is offset by mechanisms like ADAM17 inhibition, mitigating potential viral entry enhancement.
• These findings suggest a beneficial role for ARBs and ACEIs in managing COVID-19 related lung inflammation and viral interactions.