Vitamin D receptor signaling inhibits atherosclerosis in Mice

Although vitamin D has been implicated in cardiovascular protection, few studies have addressed the role of vitamin D receptor (VDR) in atherosclerosis. Here we investigate the effect of inacti-vation of the VDR signaling on atherogenesis and the antiatherosclerotic mechanism of vitamin D. Low density lipoprotein receptor (LDLR)^-/-/VDR^-/- mice exhibited site-specific accelerated atherogenesis, accompanied by increases in adhesion molecules and proinflammatory cytokines in the aorta and cholesterol influx in macrophages. Macrophages showed marked renin up-regulation in the absence of VDR, and inhibition of renin by aliskiren reduced atherosclerosis in LDLR^-/-/ VDR^-/- mice, suggesting that the renin-angiotensin system (RAS) promotes atherosclerosis in the absence of VDR. LDLR^-/- mice receiving LDLR^-/-/VDR^-/- BMT developed larger lesions than LDLR^-/- BMT controls. Moreover, LDLR^-/- mice receiving Rag-1 ^-/-/VDR^-/- BMT, which were unable to generate functional T and B lymphocytes, still had more severe atherosclerosis than Rag-1 ^-/- BMT controls, suggesting a critical role of macrophage VDR signaling in atherosclerotic suppression. Aliskiren treatment eliminated the difference in lesions between Rag-1 ^-/-/VDR^-/- BMT and Rag-1 ^-/- BMT recipients, indicating that local RAS activation in macrophages contributes to the enhanced atherogenesis seen in Rag-1 ^-/-/VDR^-/- BMT mice. Taken together, these observations provide evidence that macrophage VDR signaling, in part by suppressing the local RAS, inhibits atherosclerosis in mice.