Abstract 913: Gamma Secretase Inhibitor Reduces diet-induced Atherosclerosis in Mice by Inhibiting the Notch signaling pathway in inflammatory cells.
Background: Gamma secretase inhibitor (GSI) is known to be effective for Alzheimer’s disease. GSI also inhibits the Notch signaling pathway. Meanwhile the Notch signaling is an integral pathway for maintenance of the immune system, which would progress atherosclerotic lesions. But it remained to be determined if GSI would prevent atherogenesis.
Methods and Results: We administered GSI (LY411575 1mg/kg/day) or vehicle orally to ApoE-deficient mice with western diet for 8 weeks. In neointimal plaques of control mice, the accumulating macrophages and T cells highly expressed Notch1 as well as a downstream transcriptional factor, Hes-1. Cross sectional analysis of the aortic sinus showed that the total intimal lesion areas were significantly less in GSI-treated mice compared with control mice (control group vs. GSI group; 0.38 ± 0.04 vs. 0.21 ± 0.05 mm2; P<0.01; n=10 in each group). GSI-treated mice also showed significant reduction in fatty sclerotic lesions (control mice vs. GSI mice; 44 ± 2.8 vs. 27.3 ± 3.2 % of intimal Area; P<0.01; n=10 in each group) and decreased accumulation of macrophages and T cells in athrosclerotic intima. As reported previously, GSI-treatment resulted in the impairment of T cell differentiation in thymus and peripheral blood. In vitro study showed that GSI decreased acetylated-LDL uptake and migration of macrophages in a dose dependent manner.
Conclusion: GSI suppresses atherogenesis in ApoE-deficient mice in vivo by inhibition of Notch signaling in immune cells. Our findings indicate that GSI is a novel candidate agent to treat atherosclerosis.