γ-Secretase inhibitor reduces diet-induced atherosclerosis in apolipoprotein E-deficient mice

Atherosclerosis is a chronic inflammatory disease resulting from interactions between lipids, macrophages and arterial wall cells. The Notch signaling pathway is involved in the activation of macrophages in atherosclerotic lesions. This study examined whether pharmacological inhibition of Notch signaling using a gamma-secretase inhibitor (GSI) can reduce atherosclerotic lesion formation. Notch-related molecules were significantly increased in aortas from apolipoprotein E-deficient (ApoE(-/-)) mice. In particular, macrophages in the plaques showed strong expression of Notch1 and a downstream transcriptional factor, Hes-1. A GSI (LY411,575, 0.2, and 1.0 mg/kg/day) or vehicle control was then administered to ApoE(-/-) mice fed Western diet for 8 weeks before measuring the expression of Notch-related molecules. Systemic administration of GSI suppressed Notch signaling in vivo and reduced total plaque areas and fatty streak content in the aortic sinus in a dose-dependent manner without serious adverse effects. The GSI also suppressed the migratory activity of macrophages and reduced the expression of intercellular adhesion molecule-1, resulting in significantly decreased macrophage infiltration in the atherosclerotic plaques. These results provided new insight into the anti-atherogenic properties of GSI in Apo E-/- mice fed Western diet. (C) 2009 Elsevier Inc. All rights reserved.