PI3Kγ promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm.
JCI Insight
; 9(16)2024 Jul 18.
Article
em En
| MEDLINE
| ID: mdl-39024551
ABSTRACT
Abdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases; however, effective drug treatments are still lacking. The formation of neutrophil extracellular traps (NETs) has been shown to be a crucial trigger of AAA, and identifying upstream regulatory targets is thus key to discovering therapeutic agents for AAA. We revealed that phosphoinositide-3-kinase γ (PI3Kγ) acted as an upstream regulatory molecule and that PI3Kγ inhibition reduced NET formation and aortic wall inflammation, thereby markedly ameliorating AAA. However, the mechanism of NET formation regulated by PI3Kγ remains unclear. In this study, we showed that PI3Kγ deficiency inactivated the noncanonical pyroptosis pathway, which suppressed downstream NET formation. In addition, PI3Kγ regulation of noncanonical pyroptosis was dependent on cyclic AMP/protein kinase A signaling. These results clarify the molecular mechanism and crosstalk between PI3Kγ and NETosis in the development of AAA, potentially facilitating the discovery of therapeutic options for AAA.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aneurisma da Aorta Abdominal
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Classe Ib de Fosfatidilinositol 3-Quinase
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Armadilhas Extracelulares
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Piroptose
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Neutrófilos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
JCI Insight
Ano de publicação:
2024
Tipo de documento:
Article