Vitamin D receptor signaling inhibits atherosclerosis in Mice

Frances L. Szeto, Catherine A. Reardon, Dosuk Yoon, Youli Wang, Kari E. Wong, Yunzi Chen, Juan Kong, Shu Q. Liu, Ravi Thadhani, Godfrey S. Getz, Yan Chun Li

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1091-1101
Number of pages11
JournalMolecular Endocrinology
Volume26
Issue number7
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Szeto, F. L., Reardon, C. A., Yoon, D., Wang, Y., Wong, K. E., Chen, Y., Kong, J., Liu, S. Q., Thadhani, R., Getz, G. S., & Li, Y. C. (2012). Vitamin D receptor signaling inhibits atherosclerosis in Mice. Molecular Endocrinology, 26(7), 1091-1101. https://doi.org/10.1210/me.2011-1329