Reduction of atherosclerosis despite hypercholesterolemia in lyn-deficientmice fed a high-fat diet

Background: Oxidation and other modifications of serum low-density lipoprot ein (LDL) are associated with the development of atherosclerosis, and a sca venger receptor and CD40 signalling are also known to play important roles in the process. We previously showed that the Src family protein-tyrosine k inase Lyn is physically and/or functionally associated with macrophage type -I and type-II class-A scavenger receptors (MSR-A) and CD40. Results: In this study, we addressed whether Lyn is involved in the build-u p of serum lipid levels and in atherosclerotic changes. When fed a normal d iet, lyn-deficient mice had serum lipid levels that were no different from those of wild-type mice. By contrast, lyn-deficient mice fed a high-fat die t showed serum lipid levels that were much higher than those seen in wild-t ype mice. Curiously, however, the lyn-deficient mice fed either diet showed no increase in incidence of atherosclerotic lesions compared with wild-typ e mice. This may be partly explained by our data showing suppression of pro liferation of peritoneal macrophages in response to oxidized LDL in the abs ence of Lyn, and failure of stimulation of the CD40 pathway in lyn-deficien t macrophages to induce expression of monocytic chemoattractant protein-1 ( MCP-1), which is related to atherosclerosis. Conclusions: These results suggest that Lyn plays an important role in the metabolism of serum lipids and in the development of atherosclerotic lesion s on high-fat diets.