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Aging (Albany NY) ; 15(24): 15196-15212, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38149979

RESUMO

OBJECTIVE: Notch-1 signaling is significantly associated with the occurrence and development of atherosclerosis (AS). However, the molecular mechanisms underlying the specific deletion of Notch-1 in AS-associated macrophages are not fully understood. This study aimed to investigate the effects of Notch-1 in AS. METHODS AND RESULTS: Tissue samples were obtained from atherosclerotic segments of human carotid arteries. Immunofluorescence staining showed that Notch-1 was significantly colocalized with macrophages (CD68+), and Notch-1 staining was increased in human vulnerable plaques. Notch-1MAC-KO/ApoE-/- mice were generated in which Notch-1 was selectively inactivated in macrophages, and WT for littermate control mice (ApoE-/-/Notch-1WT). A control group was then established. All mice fed with a high-fat and Oil Red O, Movat, a-SMA, CD68, and Sirius red staining were used to evaluate the morphology. Specific deletion of Notch-1 in macrophages repressed the pathophysiology of AS. Immunofluorescent staining and Western blotting revealed that Notch-1MAC-KO repressed M1 and M2 responses in AS. Here, GSEA revealed that Notch-1 activation and PI3K signaling were statistically significantly correlated with each other, and Notch-1 was involved in the regulation of the PI3K signaling pathway. In the in vitro experiments, the secretion of Arg-1 and exosomes was classified by peritoneal macrophages of Notch-1MAC-KO/ApoE-/- and Notch-1WT/ApoE-/- mice. Immunohistochemistry staining and Western blotting were used to measure the expression levels of Notch1, PI3K, p-PI3K, AKT, p-AKT, Arg-1, IL-6, CD36, SREBP-1, CD206, iNOS, cleaved-caspase-3/-9, Bax, CD9, Alix and TSG101 in the peritoneal macrophages and exosomes, respectively. CONCLUSIONS: The specific deletion of Notch-1 in macrophage represses the formation and development of AS via the PI3K/AKT signaling pathway.


Assuntos
Aterosclerose , Macrófagos , Receptor Notch1 , Animais , Humanos , Camundongos , Anti-Inflamatórios/farmacologia , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/metabolismo
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