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Research Paper|Volume 15, Issue 24|pp 15196—15212

Macrophage-specific deletion of Notch-1 induced M2 anti-inflammatory effect in atherosclerosis via activation of the PI3K-oxidative stress axis

Mingming Zhang1, Xiangyong Yue2, Xueping Zhao3, Yonggang Lu4, Hongtao Liu1, Zhe Zhang1, Huan Ma1, Xing Wang1, Hanying Xing1
  • 1Clinical Medicine Research Center, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
  • 2Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
  • 3Department of Nursing, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
  • 4Clinical Laboratory, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
Received: April 24, 2023Accepted: November 2, 2023Published: December 26, 2023
https://doi.org/10.18632/aging.205342

Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.