Abstract 5200: Octyl-D-Carnosine Attenuates Atherogenesis in ApoE Null Mice Fed a Western Diet

Abstract

Lipid endoperoxides resulting from oxidation of unsaturated lipids are further metabolized to reactive carbonyl species (RCS), which react with proteins to generate advanced lipoxidation endproducts (ALEs). ALEs are believed to evoke an inflammatory response which participates in all stages of atherosclerosis. The endogenous dipeptide L-carnosine was shown to act as quencher of RCS derived from lipoxidation. Since it is rapidly inactivated by carnosinase, we evaluated the effect of the carnosinase-resistant octyl ester of D-carnosine (ODC, Flamma SpA, 60 mg/kg in the drinking water) vs. vehicle on the development of atherosclerosis in female apoE null mice fed a western diet (42% fat) vs. standard chow for 12 weeks. Oil red O staining of en-face aorta preparations showed a significant reduction of lipid accumulation in ODC-treated vs. untreated ApoE null mice on western diet (13.2±2.5 vs. 19.2±2.0 %, P<0.001). Morphometric evaluation of aortic lesions in sections stained with the Weigert-Van Gieson method showed significantly reduced lesion area in ODC-treated mice at the level of the aortic sinus and, particularly, of the brachiocephalic artery. ODC treatment also resulted in a more stable plaque phenotype, with less inflammation and apoptosis, and more collagen and VSMCs, resulting in reduced necrotic core formation (11.8±3.8 vs. 25.3±5.4%, P<0.0001). The gene expression level of the markers of inflammation and lesion progression F4/80, MCP-1, VCAM –1, TNF- α , IFN- γ and matrix metalloproteinase-2 and 9 and the RCS- and ALE-receptors CD36, RAGE and gelectin-3 was significantly decreased and even normalized in western diet-fed ApoE null mice treated with ODC. These data indicate that generation of RCS and ALEs from lipid peroxidation plays a major role in atherogenesis and that quenching of these compounds with a D-carnosine ester may represent a promising approach to the prevention and treatment of vascular disease.