Abstract
Notch signaling pathway, which determines cell growth, differentiation and apoptosis, also mediates inflammatory responses in macrophages. Of the 4 Notch receptors (Notch1-4), Notch3 expression is selectively increased during macrophage differentiation. Whether Notch3 mediates macrophage activation and promotes cardiometabolic disorders in vivo remains unknown. We established a macrophage-selective Notch3 intercellular domain transgenic mouse (Notch3tg) under control of the macrophage SR-A promoter/enhancer. Peritoneal macrophages of Notch3tg showed a “classical” activating (M1) phenotype (i.e. increased IL-1β and iNOS expression and decreased arginase 1 expression) and increased expression of bone morphogenetic proteins (i.e. BMP-4 and -7), which have been implicated in osteoblast differentiation. To assess the roles of macrophage-selective notch3 signaling in obesity and atherosclerosis, we generated Notch3tgLdlr-/- (n=10) and Ldlr -/- littermates (n=10) and fed these animals a high fat and high cholesterol diet for 24 weeks. Peritoneal macrophages of Notch3tgLdlr -/- promoted foam cell formation with increased expression of scavenger receptors (i.e. CD36, SR-A and LOX-1). Notch3tgLdlr-/- increased lipid-rich plaque with macrophage accumulation and vascular calcification. Notch3tgLdlr-/- showed increased epididymal and subcutaneous fat weight. In epididymal fat, Notch3tgLdlr-/- showed increased expression of leptin consistent with visceral fat accumulation. In conclusion, Notch3 signaling in macrophages activates macrophage proinflammatory function and promotes obesity, atherosclerosis and vascular calcification.
