ACE2 improves endothelial cell function and reduces acute lung injury by downregulating FAK expression.
Int Immunopharmacol
; 128: 111535, 2024 Feb 15.
Article
en En
| MEDLINE
| ID: mdl-38246001
ABSTRACT
Endothelial cell (EC) barrier dysfunction and increased adhesion of immune inflammatory cells to ECs crucially contribute to acute lung injury (ALI). Angiotensin-converting enzyme 2 (ACE2) is an essential regulator of the renin-angiotensin system (RAS) and exerts characteristic vasodilatory and anti-inflammatory effects. SARS-COV-2 infects the lungs by binding to ACE2, which can lead to dysregulation of ACE2 expression, further leading to ALI with predominantly vascular inflammation and eventually to more severe acute respiratory distress syndrome (ARDS). Therefore, restoration of ACE2 expression represents a valuable therapeutic approach for SARS-COV-2-related ALI/ARDS. In this study, we used polyinosinic-polycytidylic acid (Poly(IC)), a double-stranded RNA analog, to construct a mouse ALI model that mimics virus infection. After Poly(IC) exposure, ACE2 was downregulated in mouse lung tissues and in cultured ECs. Treatment with DIZE, an ACE2-activating compound, upregulated ACE2 expression and relieved ALI in mice. DIZE also improved barrier function and reduced the number of THP-1 monocytes adhering to cultured ECs. Focal adhesion kinase (FAK) and phosphorylated FAK (p-FAK) levels were increased in lung tissues of ALI mice as well as in Poly(IC)-treated ECs in vitro. Both DIZE and the FAK inhibitor PF562271 decreased FAK/p-FAK expression in both ALI models, attenuating ALI severity in vivo and increasing barrier function and reducing monocyte adhesion in cultured ECs. Furthermore, in vivo experiments using ANG 1-7 and the MAS inhibitor A779 corroborated that DIZE-mediated ACE2 activation stimulated the activity of the ANG 1-7/MAS axis, which inhibited FAK/p-FAK expression in the mouse lung. These findings provide further evidence that activation of ACE2 in ECs may be a valuable therapeutic strategy for ALI.
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Banco de datos:
MEDLINE
Asunto principal:
Piridinas
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Síndrome de Dificultad Respiratoria
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Sulfonamidas
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Lesión Pulmonar Aguda
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Indoles
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2024
Tipo del documento:
Article