ACE2 improves endothelial cell function and reduces acute lung injury by downregulating FAK expression

Area of Science:

• Cardiovascular Biology
• Pulmonary Medicine
• Immunology

Background:

• Endothelial cell (EC) dysfunction and immune cell adhesion drive acute lung injury (ALI).
• Angiotensin-converting enzyme 2 (ACE2) regulates the renin-angiotensin system (RAS), offering anti-inflammatory and vasodilatory benefits.
• SARS-CoV-2 infection downregulates ACE2, exacerbating ALI and potentially leading to acute respiratory distress syndrome (ARDS).

Purpose of the Study:

• To investigate the therapeutic potential of restoring ACE2 expression for ALI.
• To evaluate the efficacy of an ACE2-activating compound, DIZE, in a mouse model of ALI.
• To elucidate the underlying mechanisms involving focal adhesion kinase (FAK) and the ANG 1-7/MAS axis.

Main Methods:

• A mouse model of ALI was induced using polyinosinic-polycytidylic acid (Poly(I:C)).
• ACE2 expression, EC barrier function, and monocyte adhesion were assessed.
• The effects of DIZE, a FAK inhibitor (PF562271), ANG 1-7, and MAS inhibitor (A779) were evaluated in vivo and in vitro.

Main Results:

• Poly(I:C) exposure downregulated ACE2 and increased FAK/p-FAK levels, mimicking ALI.
• DIZE treatment upregulated ACE2, ameliorated ALI severity, improved EC barrier function, and reduced monocyte adhesion.
• DIZE and PF562271 inhibited FAK/p-FAK expression; DIZE's effects were mediated by the ANG 1-7/MAS axis.

Conclusions:

• Restoration of ACE2 expression is a promising therapeutic strategy for ALI.
• DIZE effectively treats ALI by enhancing ACE2 activity, improving endothelial barrier function, and modulating FAK signaling.
• Targeting the ACE2/ANG 1-7/MAS pathway offers a potential treatment for ALI and related conditions like ARDS.