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

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-1 MAC-KO /ApoE −/− mice were generated in which Notch-1 was selectively inactivated in macrophages, and WT for littermate control mice (ApoE −/− /Notch-1 WT ). 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-1 MAC-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-1 MAC-KO /ApoE −/− and Notch-1 WT /ApoE −/− mice. Immunohistochemistry staining and Western blotting were used to measure the expression levels of Notch1,

Unraveling the immunological roles of serum amyloid A3 in aortic immune cell subsets during atherosclerosis progression

“…Oncostatin M (OSM) signaling promotes atherogenesis and plaque vulnerability by promoting the differentiation of vascular smooth muscle cells into osteoblastic phenotypes via M1 macrophages, potentially leading to plaque instability 37 . NOTCH signaling plays a significant role in atherosclerosis development, with Notch-1 deletion inducing anti-inflammatory M2 effects through the PI3K-Akt pathway, contrasting with its increased presence in vulnerable human plaques 67 .…”