Vitamin D Receptor Signaling Inhibits Atherosclerosis in Mice

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 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.

Predictors of Subclinical Atheromatosis Progression over 2 Years in Patients with Different Stages of CKD

“…Inflammation, estimated by high ferritin levels, persists as an important risk factor for atheromatosis. Low vitamin D levels are also predictors of plaque progression, confirming previous experimental studies showing the effect of a vitamin D deficit on atheromatosis (41)(42)(43). A significant interaction between vitamin D and BMI was also found.…”

Vitamin D Suppression of Endoplasmic Reticulum Stress Promotes an Antiatherogenic Monocyte/Macrophage Phenotype in Type 2 Diabetic Patients

“…Interestingly, other studies indicate that M1 macrophages dominate advanced plaques and are considered to be proinflammatory, whereas M2 macrophages predominate in early plaques, rapidly accumulate small lipid droplets, and are anti-inflammatory, suggesting that vitamin D may induce proinflammatory effects despite suppression of macrophage cholesterol deposition (6,14,(53)(54)(55)(56). However, recent data in mice show that bone marrow transplantation of cells with the absence of the vitamin D receptor increases atherosclerosis, mediated through local activation of the renin angiotensin system in macrophages (57), suggesting that induction of the M1 macrophage phenotype by vitamin D may lead to a net beneficial effect. Additionally, M1 macrophages express membrane receptors that are associated with plaque macrophage egression (58 -61).…”

Vitamin D in Oxidative Stress and Diseases

“…Heart-VDR null mice show myocardial hypertrophy, while VDR and CYP27B1 null mice develop hypertension as well and display increased production of renin, contributing probably to early atherosclerosis onset [51]. Vitamin D 3 may protect against atherosclerosis inhibiting macrophage cholesterol uptake and foam cell formation, and reducing vascular smooth muscle cell proliferation and expression of adhesion molecules in endothelial cells.…”