3.9 Article

Vitamin D Receptor Signaling Inhibits Atherosclerosis in Mice

期刊

MOLECULAR ENDOCRINOLOGY
卷 26, 期 7, 页码 1091-1101

出版社

ENDOCRINE SOC
DOI: 10.1210/me.2011-1329

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资金

  1. National Institutes of Health [HL085793]
  2. Center for D-Receptor Activation Research
  3. Molecular and Cellular Biology Training Grant [T32 GM007183-35]
  4. Abbott Laboratories

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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 inactivation 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. (Molecular Endocrinology 26: 1091-1101, 2012)

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