Atherogenesis, atherosclerosis and vitamin D – review Dec 2013

The Role of the Intraplaque Vitamin D System in Atherogenesis

Scientifica, Volume 2013 (2013), Article ID 620504, 14 pages, http://dx.doi.org/10.1155/2013/620504
Federico Carbone 1,2 and Fabrizio Montecucco 1,3
1Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16132 Genoa, Italy
2Cardiology Division, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, 64, Avenue de la Roseraie, 1211 Geneva, Switzerland
3Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland

Vitamin D has been shown to play critical activities in several physiological pathways not involving the calcium/phosphorus homeostasis. The ubiquitous distribution of the vitamin D receptor that is expressed in a variety of human and mouse tissues has strongly supported research on these “nonclassical” activities of vitamin D. On the other hand, the recent discovery of the expression also for vitamin D-related enzymes (such as 25-hydroxyvitamin D-1α-hydroxylase and the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase) in several tissues suggested that the vitamin D system is more complex than previously shown and it may act within tissues through autocrine and paracrine pathways. This updated model of vitamin D axis within peripheral tissues has been particularly investigated in atherosclerotic pathophysiology. This review aims at updating the role of the local vitamin D within atherosclerotic plaques, providing an overview of both intracellular mechanisms and cell-to-cell interactions. In addition, clinical findings about the potential causal relationship between vitamin D deficiency and atherogenesis will be analysed and discussed.
PDF is attached at the bottom of this page

1. Introduction

Since its discovery in the early 1900s, the role of vitamin D has been limited to calcium/phosphate homeostasis through a predominant action on the kidney, intestine, and bone [1]. On the contrary, evidence in recent decades has suggested that vitamin D might play a critical role in many other metabolic pathways, referred as “nonclassical effects” [2]. Thus, vitamin D is currently under investigation in cancer [3], autoimmune disorders [4], infections [5], and neurological [6] and cardiovascular (CV) diseases. A large amount of observational studies has shown that vitamin D deficiency is associated with a wide range of CV risk factors [7], as well as poor CV outcome [8], but more recent findings from interventional trial have weakened this initial enthusiasm with a more sceptical view. Ultimately, Brandenburg correctly stated: “there should be less persuasive observational associative data, but more convincing interventional results in the field of vitamin D” [9]. Certainly, a critical analysis of literature has revealed several limitations especially in study design, but also the newer insights about the local activity of vitamin D within peripheral tissues might explain the conflicting results between interventional and observational studies. In this new research approach, 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) is emerging as a main regulator of the extrarenal vitamin D system along with the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase (CYP24A1) and vitamin D receptor (VDR). The aim of this review is to update the current evidence about the role of vitamin D in the pathophysiology of atherosclerosis and suggest a critical basis for future investigations.

2. Vitamin D Signalling

The availability of vitamin D is largely dependent on sunlight exposure (more than 80% of the requirements). In skin, ultraviolet-B (UVB) radiation induces the conversion of 7-dehydrocholesterol to the inactive precursor of vitamin D, through a photosynthetic reaction which evolved over 750 million years ago [10]. Subsequently, the 25-hydroxylation in the liver generates the 25-hydroxyvitamin D [25(OH) vitamin D or calcidiol] [11], which is biologically inactive but nonetheless used as marker of vitamin D status because of being stable, largely circulating, and easy to quantify. Calcidiol becomes active after conversion to 1,25-dihydroxyvitamin D [1,25(OH)2 vitamin D or calcitriol] which occurs through the action of CYP27B1, the rate-limiting enzyme [12]. Accordingly, CYP27B1 activity is tightly regulated with feedback control mechanisms (at least in the kidney) involving the parathyroid hormone (PTH), calcitonin, 1,25(OH)2 vitamin D itself [13], and CYP24A1 (the catabolic enzyme of vitamin D) [14]. The biological response to 1,25(OH)2 vitamin D is mediated by VDR, a DNA-binding transcription factor member of the nuclear receptor superfamily. VDR activation requires the binding to both 1,25(OH)2 vitamin D and one of retinoid X receptors (RXR α, β, or γ). Only in this heterodimeric form VDR complex recognizes the vitamin D response elements (VDRE), repeated sequences of 6 hexamers in the promoter region of target gene. Furthermore, since VDR may regulate 3% to 5% of human genome, allosteric influences, VDRE location, and epigenetic modification of DNA and histones modulate the VDR activity in the different cell types [15]. An additional feature shown by VDR (and by the whole nuclear receptor superfamily) is the ability to bind multiple lipophilic ligands, thus amplifying the vitamin D signalling activity. Interestingly, an extranuclear expression of VDR (on cell surface membrane and mitochondria) was recently discovered [16, 17] and shown to trigger nongenomic rapid responses [18].

Unlike the genomic responses (generally taking several hours till days to be fully manifest), these rapid nongenomic responses are generated in a shorter period of time (1-2 to 45 minutes). As already recognized for other steroidal hormones [19–21], plasma membrane caveolae are involved in vitamin D-induced rapid responses. Caveolae are localized within the lipid-rafts (microdomains of the plasma membrane enriched in sphingolipids and cholesterol) and might promote intracellular responses by flask-shaped membrane invagination [22]. VDR was found to be closely localized to caveolae [23], as also suggested by functional studies [24]. The VDR-caveolae complex may activate several downstream intracellular signalling cascades involving kinases, phosphatases, and ion channels as well as modulate gene expression, in a cross-talk with the classical genomic effects of vitamin D [25].

Ultimately, these recent insights, together with the ability to bind multiple lipophilic ligands (feature shared by the whole nuclear receptor superfamily), further increased complexity in vitamin D signalling pathways.

3. Vitamin D System and Atherosclerosis: Clinical Findings

Acute ischemic atherosclerotic complications are the leading cause of mortality and morbidity worldwide [26]. To date, it is commonly accepted that atherosclerotic plaque development is orchestrated by chronic low-grade inflammatory processes occurring within the arterial wall, in peripheral organs, and in the systemic circulation [27]. Endothelial dysfunction is a very early step in atherogenesis, especially at sites characterized by disturbed laminar flow. This pathophysiological event promotes subendothelial accumulation of low density lipoproteins (LDLs) [28]. Within the subintimal space of the arterial wall, LDLs (whether in native form or modified by oxidative stress) trigger inflammatory and vascular resident cells to produce several mediators attracting circulating leukocytes, including monocytes [29], neutrophils [30], and lymphocytes [31]. This chronic inflammatory process is responsible for the atherosclerotic plaque structure (including the necrotic lipid core and the fibrous cap) and promotes plaque instability [32]. Several observational studies and recent meta-analyses in humans showed that circulating 25(OH) vitamin D was inversely correlated with poor CV outcomes [8, 33, 34]. However, the first randomized clinical trials have provided even more discouraging results [34, 35]. In addition, also studies investigating the potential relationship between serum vitamin D and atherosclerotic plaque vulnerability have provided ambiguous results. For instance, studies focusing on carotid intima-media thickness (cIMT), a well-recognized biomarker of subclinical atherosclerosis also associated with a wide range of CV risk factors and CV diseases [36], showed a potential relationship between vitamin D deficiency and atherogenesis (Table 1). In particular, Deleskog and coworkers, in a longitudinal evaluation of 3,430 patients at high cardiovascular risk but without prevalent disease, failed to show an increased cIMT progression in vitamin D deficient patients when compared with the group with sufficient vitamin D [37]. On the other hand, the significant association between low vitamin D levels and a wide range of CV risk factor observed in this cohort did not prove any potential connections between vitamin D and clinical atherosclerotic outcomes. These recent findings are in accordance with previous observational studies. The research groups of Targher et al. and Liu et al. demonstrated an inverse correlation between vitamin D levels and cIMT severity [38, 39]. Among a subgroup of patients with end-stage renal disease, only Kraśniak and colleagues [40] showed a linear inverse correlation between 25(OH) vitamin D and cIMT. On the other hand, the case-control study of Briese et al. [41] and the cross-sectional analysis of Zang and coworkers [42] failed to prove any association. Likewise, in two observational cohorts of HIV-infected patients, vitamin D deficiency was showed as correlated with cIMT severity [43, 44]. However, these results were not confirmed by a recent larger simple size cross-sectional study [45]. Furthermore, recent studies (enrolling community-dwelling healthy subjects) failed to prove any relationships between vitamin D deficiency and cIMT. However, although these studies enrolled a large cohort of patients, they were designed with serious limitations. For instance, both geographical and seasonal differences in sunlight exposure might influence vitamin D status evaluation, as well as African race and old age. In addition, large simple size studies of vitamin D have been shown to underestimate other confounding factors, including differences in physical activity and dietary habits of patients, which may have significantly impacted the results [46–53]. As reported in Table 2, another CV surrogate parameter of atherogenesis (coronary artery calcium (CAC) score) has been used to investigate the potential direct association between low vitamin D levels and increased atherosclerotic plaque burden. An increased vascular calcification was previously associated with vitamin D deficiency in both experimental and clinical studies [54]. In particular, the most important clinical results were provided by the subgroup analyses from studies enrolling a large sample size. Mehrotra et al. reported a significant inverse correlation between vitamin D deficiency and CAC (prevalence and score) in patients with diabetic nephropathy [55]. On the other hand, both a recent study by Zang et al. [42] and a cross-sectional analysis from the Korean Longitudinal Study on Health and Aging did not confirm these results and failed to prove any relationships [51]. In accordance, additional cross-sectional analyses provided conflicting results [40, 46], whereas a predictive value of vitamin deficiency toward coronary calcification was supported by longitudinal studies such as the MESA (Multi-Ethnic Study of Atherosclerosis) (RR 1.38 (CI 95% 1.00–1.52); ) [56] as well as a large cohort of patients with type I diabetes mellitus (RR 6.5 (CI 95% 1.1–40.2); ) [57].

Table 1: Observational studies investigating the relationship between vitamin D and carotid intima-media thickness.

Table 2: Observational studies investigating the relationship between vitamin D and carotid artery calcification.

On the other hand, the stronger relationship between vitamin D deficiency and atherosclerosis has been demonstrated assessing endothelial dysfunction especially by flow-mediated dilatation (FMD) test (Table 3). Importantly, endothelial dysfunction is not only a predictor of future CV events [63] but also a very early marker of atherogenesis (also preceding angiographic or ultrasonic evidence of atherosclerotic plaque [64]). A large number of cross-sectional studies showed a significant and inverse correlation between vitamin D levels and ultrasound assessment of endothelial dysfunction (assessed by FMD test [60, 65–69] or measuring pulse wave velocity [62, 67, 70]), independently of other confounding parameters. In addition, the relationship between vitamin D deficiency and endothelial dysfunction was confirmed also investigating potential biochemical markers, such as interleukin (IL)-6 [65] and circulating endothelial progenitor cells [66]. Interestingly, a very recent study of Karohl and coworkers investigated the potential correlation between 25(OH) vitamin D and the coronary flow reserve (CFR) assessed by [(13)N]ammonia-positron emission tomography in asymptomatic middle-aged male twins. Low vitamin D levels were significantly correlated with CFR also in twin pairs, further supporting the role of vitamin D as a key player of endothelial function [71].

Table 3: Observational studies investigating the relationship between vitamin D and endothelial dysfunction.

Unfortunately, although observational studies support a potential causal relationship between vitamin D deficiency and atherogenesis, randomized clinical trials have so far failed to demonstrate the beneficial effects of supplementation (Table 4). Although different treatment approaches supplementing vitamin D were shown as effective in increasing plasmatic 25(OH) vitamin D concentrations, their effects on CAC were ambiguous. However, these results were mainly provided by subgroup analyses of large randomized clinical trials that were not designed to assess this primary outcome [72, 73]. Similar results were provided by treatments targeting vitamin D supplementation on endothelial function. In fact, in several randomized clinical trials (with a similar sample size) showed that a short-term supplementation with vitamin D did not clearly improve endothelial dysfunction and virtually opposite results using different methods were found [74–80].

Table 4: Interventional studies investigating the relationship between vitamin D deficiency and atherosclerosis.

4. The Intraplaque Pathophysiological Activity of Vitamin D Axis

Recent studies suggest a local activity of vitamin D by an autocrine/paracrine mechanism. Evidence in support of this new paradigm includes the discovery of the expression of CYP27B1 (rate-limiting enzyme for vitamin D synthesis) as well as the VDR in several tissues and organs [81]. In this regard, Adams and Hewison have proposed that these newly discovered features of vitamin D biology are those phylogenetically more ancient, having been found also in single cell organisms and in species lacking calcified skeleton [82]. The first recognition of an extrarenal vitamin D system dates back more than twenty-five years ago, following studies of vitamin D metabolism in pregnancy [83] and granulomatous disease sarcoidosis [84]. Afterwards, some studies with knockout mice have demonstrated the expression of CYP27B1 in several other tissues, including skin [85], prostate [86], brain [87], pancreas [88], adipose tissue [89], skeletal muscle [90], heart [91], colon [92], and neoplastic tissues [93]. In 2012, Schnatz and coworkers firstly recognized the expression of VDR within atherosclerotic plaques of premenopausal cynomolgus monkeys [94], also observing an interesting inverse correlation between plaque burden and serum 25(OH) vitamin D levels [95]. Whether VDR expression might be suppressed by plaque progression or promote atherosclerotic vulnerability has not been clarified yet. However, these results might suggest that local activation of vitamin D could be involved in the pathophysiology of atherosclerosis although the recognition of VDR source has not been investigated yet.

4.1. Vitamin D Axis and Innate Immunity

Innate immunity, especially the mononuclear cell subset, is traditionally considered the main actor in atherosclerosis. The entire vitamin D system (including the hydroxylases CYP27A1 [96, 97] and CYP27B1 [98] as well as the VDR [99] and the vitamin D catabolic enzyme 24-hydroxylase [CYP24A1] [97]) was shown to be expressed in monocyte/macrophages. Starting from the observation that VDR deletion accelerated atherogenesis in LDL receptor knockout (LDLR−/−) mice, Szeto and coworkers observed that LDLR−/−/VDR−/− bone marrow transplantation in LDLR−/− recipients mice strongly promoted atherogenesis, thus pointing out the pivotal role of mononuclear cells as a main target for the protective administration of vitamin D against atherogenesis [100]. However, a significant breakthrough in this field was previously indicated by the observation that VDR-driven gene expression was upregulated in macrophages via the concomitant activation of toll-like receptor (TLR)4 [101–103], TLR1/2 [104], and TLR coreceptor CD14 [105]. In addition, VDR is a target gene for other intracellular pathways (such as those mediated by IL-15, which are involved in monocyte differentiation to macrophages [106]) and the T lymphocyte-released cytokines interferon (IFN)-γ [103] and IL-4 [107]. Interestingly, the local overexpression of 1,25(OH)2 vitamin D was shown to promote the inflammatory response enhancing the transcription of antimicrobial peptides (AMPsβ-defensin 2 and cathelicidin) [108] and stimulating autophagy in atherosclerosis [109, 110] via a feedback mechanism [111]. On the other hand, vitamin D deficiency is associated with a pro-atherogenic monocyte phenotype (shift from M1 to M2 subtype) characterized by increased NF-κB activity and TLR expression as well as enhanced endoplasmic reticulum stress and increased expression of adhesion molecules and proinflammatory cytokines [110, 112, 113]. Conversely, the activation of vitamin D signalling improves the macrophage response to lipid overload. Downregulating the expression of CD36 and the scavenger receptor (SR)-A1, 1,25(OH)2 vitamin D decreased the uptake of oxidized and acetylated LDLs and then the foam cell formation [114, 115]. In addition, 1,25(OH)2 vitamin D decreased cholesteryl ester formation and promoted a cholesterol efflux from macrophage in addition to suppressing their migration by downregulating the chemokine receptor CCR2 [116].

On the other hand, the role of neutrophils in atherogenesis and related disease has been unknown for long time, even because of being difficult to be recognized for of their short life-span and their plastic and dynamic properties [117]. Likewise, only recently, CYP27B1 has been discovered in neutrophils [118], whereas VDR expression was already detected [119]. Similar to mononuclear cells, an increased expression of VDR and CYP27B1 may act by a feedback mechanism on activated neutrophils, decreasing the synthesis of proinflammatory molecules, such as CXCL8 [119], macrophage inflammatory protein (MIP)-1β, IL-1β, and vascular endothelial growth factor.

4.2. Vitamin D Axis and Adaptive Immunity

Through their role of antigen presenting cells, dendritic cells (DCs) are essential for both innate and adaptive immune systems functioning [120]. DCs have been largely recognized in the wall of healthy arteries, but their role in atherogenesis still remains unclear [121]. As reported by Gautier and colleagues, the transplantation of apoptosis-resistant DCs in LDLR−/− recipients mice failed to accelerate plaque progression, despite the fact that this experimental model exhibited a proatherogenic pattern characterized by increased T-cell activation (with a shift toward the proatherogenic Th1 phenotype) and a rise in circulating levels of antibodies against oxidized LDL (oxLDL) [122]. Conversely, a reduced atherosclerotic burden was directly correlated with a reduced DC recruitment (as observed in mice lacking CXC3R1, CCL2, and CCR5 [123–125]). DCs are a major source of vitamin D since they constitutively express high level of CYP27B1, that are enhanced after TLR stimulation (both TLR4 [126] and TLR1/2 [106, 127]). Through an autocrine loop, 1,25(OH)2 vitamin D was shown to suppress DC differentiation/activation up to induce a regression of differentiated DCs toward a more immature stage [128]. Additional effects of 1,25(OH)2 vitamin D on DCs include impairment on cell chemotaxis [128] and suppression of proinflammatory cytokines (e.g., IL-1 and tumor necrosis factor-α). In addition, 1,25(OH)2 vitamin D might promote a more tolerogenic phenotype of DCs decreasing the expression of class 2 MHC molecules, CD40, CD80, and CD86 [129, 130].

On the other hand, the regression of atherosclerotic burden induced by 1,25(OH)2 vitamin D might occur also via a direct effect on T cells [131–133] and this is consistent with several lines of evidence supporting atherosclerosis as a T-cell-driven disease [134]. Targeting more than 102 genes in CD4+ T cells, 1,25(OH)2 vitamin D-VDR signalling might importantly regulate T-cell activity, especially the T-helper (Th) polarization, skewing from the proinflammatory phenotype Th1 and Th17 (by suppressing IFN-γ, IL-2, and IL-17) towards an anti-inflammatory Th2 phenotype (by promoting IL-4 and IL-5 gene transcription) [135]. In addition, a recent study by Yadav and colleagues has demonstrated an association between vitamin D deficiency to an increased CD4+ CD28+ T-lymphocyte count [136] (a proatherogenic T-cell subtype) [137].

Interestingly, following the discovery that FOXP3 transcription is directly targeted by VDR [138], also some beneficial effects of vitamin D might involve the regulatory T-cell (Treg) subtype [139–141] that has been described to reduce atherosclerosis [131–133].

Overall, the immunomodulation exerted by locally activated vitamin D system on the adaptive immune system relies not only on an autocrine loop (in addition to DCs, CYP27B1 has been recognized also in T cells [142]) but especially on a paracrine effect regulated by a complex cross-talks between different cell types (for instance the combined stimulation with CD40/CD40 ligand and cytokines is the strongest inducer of CYP27B1 synthesis in DCs [143]).

4.3. The Potential Interactions between Vitamin D and Other Endocrine Pathways

Molecular and cellular mechanisms of atherogenesis and atheroprogression were shown to involve the upregulation of several neurohormonal mediators. One of the best-known hormonal axes is the renin angiotensin aldosterone system (RAAS). In particular through angiotensin II, RAAS was shown to increase vascular injury by enhancing the oxidative stress-mediated pathways and systemic inflammatory responses [144]. Moreover, a local vascular activity of RAAS has been also suggested by the detection of the expression of the angiotensin converting enzyme within atherosclerotic lesions [145]. Vitamin D is a well-known negative regulator of RAAS [146, 147] and this feature is emerging as potential pathway potentially involved in vascular injury prevention. By deleting VDR gene in LDLr−/− mice, Szeto and coworkers firstly suggested that inhibition of macrophage VDR signalling in atherosclerotic mice also suppressed the RAAS [100]. Further studies by Ish-Shalom and colleagues and Weng and coworkers have recently supported these findings in mice [148, 149]. In addition, the discovery of fibroblast growth factor (FGF)23/klotho axis has also broadened the potential role of vitamin D on the endocrine signalling in the pathogenesis of atherosclerosis. FGF23 was shown to act as counterregulatory hormone of vitamin D, suppressing both renal and extrarenal synthesis of CYP27B1 as well as enhancing the expression of catabolic enzyme CYP24A1. FGF23 is also a well-recognized risk factor for CV diseases and CV mortality [150, 151]. In addition, evidence of its direct role in promoting atherosclerosis also in patients with preserved renal function was also demonstrated [152]. Although the molecular mechanisms underlying both FGF23 and vitamin D still require to be clarified [153], recent pathophysiological studies have shown potential biphasic cardiovascular effects of these mediators in atherogenesis associated with chronic renal diseases [154].

5. Conclusions

In the last decades, the scientific debate on the CV effects of vitamin D system and the potential CV risk associated with its deficiency raised controversial findings [155]. Even if the results from the first randomized clinical trials were discouraging, these studies were not considered conclusive at all, due to limitations in study design and different compounds administered. Poor stratification by age, race, geographic position, physical activity, and sunlight exposure were the main confounding factors, in addition to the small sample size of cohorts. Moreover, the current definitions of the optimal vitamin D level in humans are bone-driven and not assessed from a cardiovascular point of view. In addition, the different compounds used for vitamin D supplementation (comprising both inactive forms of vitamin D and direct VDR agonists) may affect the reliability of these results.

On the other hand, the contribution of the local activated vitamin D system within atherosclerotic plaque has not been appropriately investigated yet. Therefore, both basic research studies and clinical trials are needed for better elucidating the therapeutic and pathophysiological role of vitamin D in atherogenesis and CV diseases.

Acknowledgment; This work was supported by the Swiss National Science Foundation Grant (no. 32003B_134963/1) to Dr. Fabrizio Montecucco.

References

(hopefully the #‘s are correct)

  1. T. B. Heaton, “On the vitamin D,” The Biochemical Journal, vol. 16, no. 6, pp. 800–808, 1922.
  2. D. Bikle, “Nonclassic actions of vitamin D,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 1, pp. 26–34, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. A. V. Krishnan, D. L. Trump, C. S. Johnson, and D. Feldman, “The role of vitamin D in cancer prevention and treatment,” Endocrinology and Metabolism Clinics of North America, vol. 39, no. 2, pp. 401–418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. L. L. Ritterhouse, S. R. Crowe, T. B. Niewold et al., “Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 70, no. 9, pp. 1569–1574, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. C. F. Gunville, P. M. Mourani, and A. A. Ginde, “The role of vitamin D in prevention and treatment of infection,” Inflammation and Allergy Drug Targets, vol. 12, no. 4, pp. 239–245, 2013. View at Publisher · View at Google Scholar
  6. C. Balion, L. E. Griffith, L. Strifler et al., “Vitamin D, cognition, and dementia: a systematic review and meta-analysis,” Neurology, vol. 79, no. 13, pp. 1397–1405, 2012. View at Publisher · View at Google Scholar
  7. J. Parker, O. Hashmi, D. Dutton et al., “Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis,” Maturitas, vol. 65, no. 3, pp. 225–236, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. L. Wang, Y. Song, J. E. Manson et al., “Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies,” Circulation, vol. 5, no. 6, pp. 819–829, 2012. View at Publisher · View at Google Scholar
  9. V. M. Brandenburg, M. G. Vervloet, and N. Marx, “The role of vitamin D in cardiovascular disease: from present evidence to future perspectives,” Atherosclerosis, vol. 225, no. 2, pp. 253–263, 2012. View at Publisher · View at Google Scholar
  10. M. F. Holick, “Evolutionary biology and pathology of vitamin D,” Journal of Nutritional Science and Vitaminology, pp. 79–83, 1992. View at Scopus
  11. J. G. Zhu, J. T. Ochalek, M. Kaufmann, G. Jones, and H. F. Deluca, “CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 39, pp. 15650–15655, 2013. View at Publisher · View at Google Scholar
  12. I. Schuster, “Cytochromes P450 are essential players in the vitamin D signaling system,” Biochimica et Biophysica Acta, vol. 1814, no. 1, pp. 186–199, 2011. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Murayama, K. Takeyama, S. Kitanaka et al., “Positive and negative regulations of the renal 25-hydroxyvitamin D3 1α-hydroxylase gene by parathyroid hormone, calcitonin, and 1α,25(OH)2D3 in intact animals,” Endocrinology, vol. 140, no. 5, pp. 2224–2231, 1999. View at Scopus
  14. R. Bland, D. Zehnder, and M. Hewison, “Expression of 25-hydroxyvitamin D3-1α-hydroxylase along the nephron: new insights into renal vitamin D metabolism,” Current Opinion in Nephrology and Hypertension, vol. 9, no. 1, pp. 17–22, 2000. View at Publisher · View at Google Scholar · View at Scopus
  15. M. R. Haussler, G. K. Whitfield, I. Kaneko et al., “Molecular mechanisms of vitamin D action,” Calcified Tissue International, vol. 92, no. 2, pp. 77–98, 2013. View at Publisher · View at Google Scholar
  16. I. Nemere, M. C. Dormanen, M. W. Hammond, W. H. Okamura, and A. W. Norman, “Identification of a specific binding protein for 1α,25-dihydroxyvitamin D3 in basal-lateral membranes of chick intestinal epithelium and relationship to transcaltachia,” The Journal of Biological Chemistry, vol. 269, no. 38, pp. 23750–23756, 1994. View at Scopus
  17. V. González Pardo, R. Boland, and A. R. de Boland, “Vitamin D receptor levels and binding are reduced in aged rat intestinal subcellular fractions,” Biogerontology, vol. 9, no. 2, pp. 109–118, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. M. R. Haussler, P. W. Jurutka, M. Mizwicki, and A. W. Norman, “Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms,” Best Practice and Research, vol. 25, no. 4, pp. 543–559, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. L. B. Lutz, M. Jamnongjit, W. Yang, D. Jahani, A. Gill, and S. R. Hammes, “Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands,” Molecular Endocrinology, vol. 17, no. 6, pp. 1106–1116, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. E. R. Levin, “Integration of the extranuclear and nuclear actions of estrogen,” Molecular Endocrinology, vol. 19, no. 8, pp. 1951–1959, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. G. E. Callera, A. Yogi, A. M. Briones et al., “Vascular proinflammatory responses by aldosterone are mediated via c-Src trafficking to cholesterol-rich microdomains: role of PDGFR,” Cardiovascular Research, vol. 91, no. 4, pp. 720–731, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. M. T. Mizwicki and A. W. Norman, “The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling,” Science Signaling, vol. 2, no. 75, article re4, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. J. A. Huhtakangas, C. J. Olivera, J. E. Bishop, L. P. Zanello, and A. W. Norman, “The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1α,25(OH)2-vitamin D3 in vivo and in vitro,” Molecular Endocrinology, vol. 18, no. 11, pp. 2660–2671, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Boscher and I. R. Nabi, “CAVEOLIN-1: role in cell signaling,” Advances in Experimental Medicine and Biology, vol. 729, pp. 29–50, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. P. W. Jurutka, P. D. Thompson, G. K. Whitfield et al., “Molecular and functional comparison of 1,25-dihydroxyvitamin D3 and the novel vitamin D receptor ligand, lithocholic acid, in activating transcription of cytochrome P450 3A4,” Journal of Cellular Biochemistry, vol. 94, no. 5, pp. 917–943, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. B. Dahlöf, “Cardiovascular disease risk factors: epidemiology and risk assessment,” The American Journal of Cardiology, vol. 105, no. 1, supplement, pp. 3A–9A, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. K. J. Woollard, “Immunological aspects of atherosclerosis,” Clinical Science, vol. 125, no. 5, pp. 221–235, 2013. View at Publisher · View at Google Scholar
  28. C. Hahn and M. A. Schwartz, “Mechanotransduction in vascular physiology and atherogenesis,” Nature Reviews Molecular Cell Biology, vol. 10, no. 1, pp. 53–62, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. F. K. Swirski, M. J. Pittet, M. F. Kircher et al., “Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 27, pp. 10340–10345, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. P. Rotzius, S. Thams, O. Soehnlein et al., “Distinct infiltration of neutrophils in lesion shoulders in ApoE-/- mice,” The American Journal of Pathology, vol. 177, no. 1, pp. 493–500, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. E. Profumo, B. Buttari, L. Saso, R. Capoano, B. Salvati, and R. Rigano, “T lymphocyte autoreactivity in inflammatory mechanisms regulating atherosclerosis,” The Scientific World Journal, vol. 2012, Article ID 157534, 9 pages, 2012. View at Publisher · View at Google Scholar
  32. G. Stoll and M. Bendszus, “Inflammation and atherosclerosis: novel insights into plaque formation and destabilization,” Stroke, vol. 37, no. 7, pp. 1923–1932, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Zittermann, S. Iodice, S. Pilz, W. B. Grant, V. Bagnardi, and S. Gandini, “Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies,” The American Journal of Clinical Nutrition, vol. 95, no. 1, pp. 91–100, 2012. View at Publisher · View at Google Scholar · View at Scopus
  34. I. R. Reid and M. J. Bolland, “Role of vitamin D deficiency in cardiovascular disease,” Heart, vol. 98, no. 8, pp. 609–614, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. S. I. Sokol, P. Tsang, V. Aggarwal, M. L. Melamed, and V. S. Srinivas, “Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis,” Cardiology in Review, vol. 19, no. 4, pp. 192–201, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Bauer, S. Caviezel, A. Teynor, R. Erbel, A. A. Mahabadi, and A. Schmidt-Trucksass, “Carotid intima-media thickness as a biomarker of subclinical atherosclerosis,” Swiss Medical Weekly, vol. 142, Article ID w13705, 2012.
  37. A. Deleskog, O. Piksasova, A. Silveira et al., “Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 11, pp. 2633–2638, 2013. View at Publisher · View at Google Scholar
  38. G. Targher, L. Bertolini, R. Padovani et al., “Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients,” Clinical Endocrinology, vol. 65, no. 5, pp. 593–597, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. J. X. Liu, J. Xiang, R. F. Bu, W. J. Wu, H. Shen, and X. J. Wang, “Serum 25-hydroxyvitamin D concentration is negatively related to carotid artery intima-media thickness in type 2 diabetic patients,” Zhonghua Xin Xue Guan Bing Za Zhi, vol. 40, no. 2, pp. 115–119, 2012.
  40. A. Kraśniak, M. Drozdz, M. Pasowicz et al., “Factors involved in vascular calcification and atherosclerosis in maintenance haemodialysis patients,” Nephrology Dialysis Transplantation, vol. 22, no. 2, pp. 515–521, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Briese, S. Wiesner, J. C. Will et al., “Arterial and cardiac disease in young adults with childhood-onset end-stage renal disease—impact of calcium and vitamin D therapy,” Nephrology Dialysis Transplantation, vol. 21, no. 7, pp. 1906–1914, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. L. Zang, P. Fu, Y. Q. Huang et al., “Vitamin D deficiency and carotid artery intima-media thickness and coronary calcification in patients with diabetic nephropathy,” Sichuan Da Xue Xue Bao Yi Xue Ban, vol. 43, no. 3, pp. 420–424, 450, 2012.
  43. A. I. Choi, J. C. Lo, K. Mulligan et al., “Association of vitamin D insufficiency with carotid intima-media thickness in HIV-infected persons,” Clinical Infectious Diseases, vol. 52, no. 7, pp. 941–944, 2011. View at Publisher · View at Google Scholar · View at Scopus
  44. A. C. Ross, S. Judd, M. Kumari et al., “Vitamin D is linked to carotid intima-media thickness and immune reconstitution in HIV-positive individuals,” Antiviral Therapy, vol. 16, no. 4, pp. 555–563, 2011. View at Publisher · View at Google Scholar · View at Scopus
  45. C. M. Shikuma, T. Seto, C. Y. Liang et al., “Vitamin D levels and markers of arterial dysfunction in HIV,” AIDS Research and Human Retroviruses, vol. 28, no. 8, pp. 793–797, 2012. View at Publisher · View at Google Scholar
  46. E. D. Michos, E. A. Streeten, K. A. Ryan et al., “Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the old order amish,” Calcified Tissue International, vol. 84, no. 3, pp. 195–202, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. S. Pilz, R. M. A. Henry, M. B. Snijder et al., “25-Hydroxyvitamin D is not associated with carotid intima-media thickness in older men and women,” Calcified Tissue International, vol. 84, no. 5, pp. 423–424, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. J. P. Reis, D. von Mühlen, E. D. Michos et al., “Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis,” Atherosclerosis, vol. 207, no. 2, pp. 585–590, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Richart, L. Thijs, T. Nawrot et al., “The metabolic syndrome and carotid intima-media thickness in relation to the parathyroid hormone to 25-OH-D3 ratio in a general population,” The American Journal of Hypertension, vol. 24, no. 1, pp. 102–109, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. A. L. Carrelli, M. D. Walker, H. Lowe et al., “Vitamin D deficiency is associated with subclinical carotid atherosclerosis: the Northern Manhattan study,” Stroke, vol. 42, no. 8, pp. 2240–2245, 2011. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Lim, H. Shin, M. J. Kim et al., “Vitamin D inadequacy is associated with significant coronary artery stenosis in a community-based elderly cohort: the Korean longitudinal study on health and aging,” Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 1, pp. 169–178, 2012. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Knox, P. Welsh, V. Bezlyak et al., “25-Hydroxyvitamin D is lower in deprived groups, but is not associated with carotid intima media thickness or plaques: results from pSoBid,” Atherosclerosis, vol. 223, no. 2, pp. 437–441, 2012. View at Publisher · View at Google Scholar
  53. M. Blondon, M. Sachs, A. N. Hoofnagle et al., “25-hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the multi-ethnic study of atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, 2013. View at Publisher · View at Google Scholar
  54. A. Zittermann, S. S. Schleithoff, and R. Koerfer, “Vitamin D and vascular calcification,” Current Opinion in Lipidology, vol. 18, no. 1, pp. 41–46, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. R. Mehrotra, D. Kermah, M. Budoff et al., “Hypovitaminosis D in chronic kidney disease,” Clinical Journal of the American Society of Nephrology, vol. 3, no. 4, pp. 1144–1151, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. I. H. de Boer, B. Kestenbaum, A. B. Shoben, E. D. Michos, M. J. Sarnak, and D. S. Siscovick, “25-Hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification,” Journal of the American Society of Nephrology, vol. 20, no. 8, pp. 1805–1812, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. K. A. Young, J. K. Snell-Bergeon, R. G. Naik et al., “Vitamin D deficiency and coronary artery calcification in subjects with type 1 diabetes,” Diabetes Care, vol. 34, no. 2, pp. 454–458, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. A. Hajas, J. Sandor, L. Csathy et al., “Vitamin D insufficiency in a large MCTD population,” Autoimmunity Reviews, vol. 10, no. 6, pp. 317–324, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. L. Pacifico, C. Anania, J. F. Osborn et al., “Low 25(OH)D3 levels are associated with total adiposity, metabolic syndrome, and hypertension in Caucasian children and adolescents,” European Journal of Endocrinology, vol. 165, no. 4, pp. 603–611, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. F. Oz, A. Y. Cizgici, H. Oflaz et al., “Impact of vitamin D insufficiency on the epicardial coronary flow velocity and endothelial function,” Coronary Artery Disease, vol. 24, no. 5, pp. 392–397, 2013. View at Publisher · View at Google Scholar
  61. A. N. Kiani, H. Fang, L. S. Magder, and M. Petri, “Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima-media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus,” Rheumatology, 2013. View at Publisher · View at Google Scholar
  62. G. Sypniewska, J. Pollak, P. Strozecki et al., “25-hydroxyvitamin D, biomarkers of endothelial dysfunction and subclinical organ damage in adults with hypertension,” The American Journal of Hypertension, vol. 27, no. 1, pp. 114–121, 2014. View at Publisher · View at Google Scholar
  63. Y. Inaba, J. A. Chen, and S. R. Bergmann, “Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis,” International Journal of Cardiovascular Imaging, vol. 26, no. 6, pp. 631–640, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Charakida, S. Masi, T. F. Lüscher, J. J. P. Kastelein, and J. E. Deanfield, “Assessment of atherosclerosis: the role of flow-mediated dilatation,” European Heart Journal, vol. 31, no. 23, pp. 2854–2861, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. K. L. Jablonski, M. Chonchol, G. L. Pierce, A. E. Walker, and D. R. Seals, “25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults,” Hypertension, vol. 57, no. 1, pp. 63–69, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. F. Yiu, Y. H. Chan, K. H. Yiu et al., “Vitamin D deficiency is associated with depletion of circulating endothelial progenitor cells and endothelial dysfunction in patients with type 2 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 5, pp. E830–E835, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. I. Al Mheid, R. Patel, J. Murrow et al., “Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans,” Journal of the American College of Cardiology, vol. 58, no. 2, pp. 186–192, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. N. Chitalia, A. Recio-Mayoral, J. C. Kaski, and D. Banerjee, “Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients,” Atherosclerosis, vol. 220, no. 1, pp. 265–268, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. S. K. Syal, A. Kapoor, E. Bhatia et al., “Vitamin D deficiency, coronary artery disease, and endothelial dysfunction: observations from a coronary angiographic study in Indian patients,” The Journal of Invasive Cardiology, vol. 24, no. 8, pp. 385–389, 2012.
  70. O. Kuloglu, M. Gur, T. Seker et al., “Serum 25-hydroxyvitamin D level is associated with arterial stiffness, left ventricle hypertrophy, and inflammation in newly diagnosed hypertension,” Journal of Investigative Medicine, vol. 61, no. 6, pp. 989–994, 2013.
  71. C. Karohl, V. Vaccarino, E. Veledar et al., “Vitamin D status and coronary flow reserve measured by positron emission tomography: a co-twin control study,” Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 1, pp. 389–397, 2013. View at Publisher · View at Google Scholar
  72. J. E. Manson, M. A. Allison, J. J. Carr et al., “Calcium/vitamin D supplementation and coronary artery calcification in the Women's health initiative,” Menopause, vol. 17, no. 4, pp. 683–691, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. P. Raggi, G. M. Chertow, P. U. Torres et al., “The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis,” Nephrology Dialysis Transplantation, vol. 26, no. 4, pp. 1327–1339, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. J. A. Sugden, J. I. Davies, M. D. Witham, A. D. Morris, and A. D. Struthers, “Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels,” Diabetic Medicine, vol. 25, no. 3, pp. 320–325, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. O. Tarcin, D. G. Yavuz, B. Ozben et al., “Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 10, pp. 4023–4030, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. M. D. Witham, F. J. Dove, M. Dryburgh, J. A. Sugden, A. D. Morris, and A. D. Struthers, “The effect of different doses of vitamin D3 on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial,” Diabetologia, vol. 53, no. 10, pp. 2112–2119, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Shab-Bidar, T. R. Neyestani, A. Djazayery et al., “Regular consumption of vitamin D-fortified yogurt drink (Doogh) improved endothelial biomarkers in subjects with type 2 diabetes: a randomized double-blind clinical trial,” BMC Medicine, vol. 9, article 125, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. M. D. Witham, F. J. Dove, J. A. Sugden, A. S. Doney, and A. D. Struthers, “The effect of vitamin D replacement on markers of vascular health in stroke patients—a randomised controlled trial,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 22, no. 10, pp. 864–870, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. H. Stricker, F. T. Bianda, S. Guidicelli-Nicolosi, C. Limoni, and G. Colucci, “Effect of a single, oral, high-dose vitamin D supplementation on endothelial function in patients with peripheral arterial disease: a randomised controlled pilot study,” European Journal of Vascular and Endovascular Surgery, vol. 44, no. 3, pp. 307–312, 2012. View at Publisher · View at Google Scholar
  80. Y. F. Yiu, K. H. Yiu, C. W. Siu et al., “Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes,” Atherosclerosis, vol. 227, no. 1, pp. 140–146, 2013. View at Publisher · View at Google Scholar
  81. D. K. Panda, D. Miao, M. L. Tremblay et al., “Targeted ablation of the 25-hydroxyvitamin D 1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7498–7503, 2001. View at Publisher · View at Google Scholar · View at Scopus
  82. J. S. Adams and M. Hewison, “Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase,” Archives of Biochemistry and Biophysics, vol. 523, no. 1, pp. 95–102, 2012. View at Publisher · View at Google Scholar · View at Scopus
  83. T. K. Gray, G. E. Lester, and R. S. Lorenc, “Evidence for extra-renal 1 α-hydroxylation of 25-hydroxyvitamin D3 in pregnancy,” Science, vol. 204, no. 4399, pp. 1311–1313, 1979. View at Scopus
  84. G. L. Barbour, J. W. Coburn, E. Slatopolsky, A. W. Norman, and R. L. Horst, “Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D,” The New England Journal of Medicine, vol. 305, no. 8, pp. 440–443, 1981. View at Scopus
  85. J. N. Flanagan, L. W. Whitlatch, T. C. Chen et al., “Enhancing 1α-hydroxylase activity with the 25-hydroxyvitamin D-1α-hydroxylase gene in cultured human keratinocytes and mouse skin,” Journal of Investigative Dermatology, vol. 116, no. 6, pp. 910–914, 2001. View at Publisher · View at Google Scholar · View at Scopus
  86. T. C. Chen, L. Wang, L. W. Whitlatch, J. N. Flanagan, and M. F. Holick, “Prostatic 25-hydroxyvitamin D-1 α-hydroxylase and its implication in prostate cancer,” Journal of Cellular Biochemistry, vol. 88, no. 2, pp. 315–322, 2003. View at Publisher · View at Google Scholar · View at Scopus
  87. D. W. Eyles, S. Smith, R. Kinobe, M. Hewison, and J. J. McGrath, “Distribution of the Vitamin D receptor and 1α-hydroxylase in human brain,” Journal of Chemical Neuroanatomy, vol. 29, no. 1, pp. 21–30, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. R. Bland, D. Markovic, C. E. Hills et al., “Expression of 25-hydroxyvitamin D3-1α-hydroxylase in pancreatic islets,” Journal of Steroid Biochemistry and Molecular Biology, vol. 89-90, pp. 121–125, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Li, M. E. Byrne, E. Chang et al., “1α,25-Dihydroxyvitamin D hydroxylase in adipocytes,” Journal of Steroid Biochemistry and Molecular Biology, vol. 112, no. 1–3, pp. 122–126, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. R. Srikuea, X. Zhang, O. K. Park-Sarge, and K. A. Esser, “VDR and CYP27B1 are expressed in C2C12 cells and regenerating skeletal muscle: potential role in suppression of myoblast proliferation,” The American Journal of Physiology—Cell Physiology, vol. 303, no. 4, pp. 396–405, 2012. View at Publisher · View at Google Scholar
  91. S. Chen, D. J. Glenn, W. Ni et al., “Expression of the vitamin D receptor is increased in the hypertrophic heart,” Hypertension, vol. 52, no. 6, pp. 1106–1112, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. V. Lagishetty, R. F. Chun, N. Q. Liu, T. S. Lisse, J. S. Adams, and M. Hewison, “1α-hydroxylase and innate immune responses to 25-hydroxyvitamin D in colonic cell lines,” Journal of Steroid Biochemistry and Molecular Biology, vol. 121, no. 1-2, pp. 228–233, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. K. Townsend, K. N. Evans, M. J. Campbell, K. W. Colston, J. S. Adams, and M. Hewison, “Biological actions of extra-renal 25-hydroxyvitamin D-1α-hydroxylase and implications for chemoprevention and treatment,” Journal of Steroid Biochemistry and Molecular Biology, vol. 97, no. 1-2, pp. 103–109, 2005. View at Publisher · View at Google Scholar · View at Scopus
  94. P. F. Schnatz, M. Nudy, D. M. O'Sullivan et al., “The quantification of vitamin D receptors in coronary arteries and their association with atherosclerosis,” Maturitas, vol. 73, no. 2, pp. 143–147, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. P. F. Schnatz, M. Nudy, D. M. O'Sullivan et al., “The quantification of vitamin D receptors in coronary arteries and their association with atherosclerosis,” Maturitas, vol. 19, no. 9, pp. 967–973, 2012. View at Publisher · View at Google Scholar · View at Scopus
  96. C. M. Quinn, W. Jessup, J. Wong, L. Kritharides, and A. J. Brown, “Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: a role for RXR and PPARγ ligands,” Biochemical Journal, vol. 385, no. 3, pp. 823–830, 2005. View at Publisher · View at Google Scholar · View at Scopus
  97. E. Gottfried, M. Rehli, J. Hahn, E. Holler, R. Andreesen, and M. Kreutz, “Monocyte-derived cells express CYP27A1 and convert vitamin D3 into its active metabolite,” Biochemical and Biophysical Research Communications, vol. 349, no. 1, pp. 209–213, 2006. View at Publisher · View at Google Scholar · View at Scopus
  98. J. S. Adams, T. G. Beeker, T. Hongo, and T. L. Clemens, “Constitutive expression of a vitamin D 1-hydroxylase in a myelomonocytic cell line: a model for studying 1,25-dihydroxyvitamin D production in vitro,” Journal of Bone and Mineral Research, vol. 5, no. 12, pp. 1265–1269, 1990. View at Scopus
  99. D. M. Provvedini, C. D. Tsoukas, L. J. Deftos, and S. C. Manolagas, “1,25-dihydroxyvitamin D3 receptors in human leukocytes,” Science, vol. 221, no. 4616, pp. 1181–1183, 1983. View at Scopus
  100. F. L. Szeto, C. A. Reardon, D. Yoon et al., “Vitamin D receptor signaling inhibits atherosclerosis in mice,” Molecular Endocrinology, vol. 26, no. 7, pp. 1091–1101, 2012. View at Publisher · View at Google Scholar
  101. K. N. Evans, H. Taylor, D. Zehnder et al., “Increased expression of 25-hydroxyvitamin D-1 αhydroxylase in dysgerminomas: a novel form of humoral hypercalcemia of malignancy,” The American Journal of Pathology, vol. 165, no. 3, pp. 807–813, 2004. View at Scopus
  102. K. N. Evans, L. Nguyen, J. Chan et al., “Effects of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D 3 on cytokine production by human decidual cells,” Biology of Reproduction, vol. 75, no. 6, pp. 816–822, 2006. View at Publisher · View at Google Scholar · View at Scopus
  103. K. Stoffels, L. Overbergh, A. Giulietti, L. Verlinden, R. Bouillon, and C. Mathieu, “Immune regulation of 25-hydroxyvitamin-D3-1α-hydroxylase in human monocytes,” Journal of Bone and Mineral Research, vol. 21, no. 1, pp. 37–47, 2006. View at Publisher · View at Google Scholar · View at Scopus
  104. P. T. Liu, S. Stenger, H. Li et al., “Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response,” Science, vol. 311, no. 5768, pp. 1770–1773, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. F. Oberg, J. Botling, and K. Nilsson, “Functional antagonism between vitamin D3 and retinoic acid in the regulation of CD14 and CD23 expression during monocytic differentiation of U-937 cells,” Journal of Immunology, vol. 150, no. 8, part 1, pp. 3487–3495, 1993. View at Scopus
  106. S. R. Krutzik, M. Hewison, P. T. Liu et al., “IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway,” Journal of Immunology, vol. 181, no. 10, pp. 7115–7120, 2008. View at Scopus
  107. K. Edfeldt, P. T. Liu, R. Chun et al., “T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 52, pp. 22593–22598, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. T. T. Wang, F. P. Nestel, V. Bourdeau et al., “Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression,” Journal of Immunology, vol. 173, no. 5, pp. 2909–2912, 2004. View at Scopus
  109. J. M. Yuk, D. M. Shin, H. M. Lee et al., “Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin,” Cell Host and Microbe, vol. 6, no. 3, pp. 231–243, 2009. View at Publisher · View at Google Scholar · View at Scopus
  110. S. Devaraj, J. M. Yun, C. R. Duncan-Staley, and I. Jialal, “Low vitamin d levels correlate with the proinflammatory state in type 1 diabetic subjects with and without microvascular complications,” The American Journal of Clinical Pathology, vol. 135, no. 3, pp. 429–433, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. L. Helming, J. Böse, J. Ehrchen et al., “1α,25-dihydroxyvitamin D3 is a potent suppressor of interferon γ-mediated macrophage activation,” Blood, vol. 106, no. 13, pp. 4351–4358, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. A. Giulietti, E. van Etten, L. Overbergh, K. Stoffels, R. Bouillon, and C. Mathieu, “Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-dihydroxyvitamin D3 works as anti-inflammatory,” Diabetes Research and Clinical Practice, vol. 77, no. 1, pp. 47–57, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. A. E. Riek, J. Oh, J. E. Sprague et al., “Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients,” The Journal of Biological Chemistry, vol. 287, no. 46, pp. 38482–38494, 2012. View at Publisher · View at Google Scholar
  114. J. Oh, S. Weng, S. K. Felton et al., “1,25(OH)2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus,” Circulation, vol. 120, no. 8, pp. 687–698, 2009. View at Publisher · View at Google Scholar · View at Scopus
  115. A. E. Riek, J. Oh, and C. Bernal-Mizrachi, “Vitamin D regulates macrophage cholesterol metabolism in diabetes,” Journal of Steroid Biochemistry and Molecular Biology, vol. 121, no. 1-2, pp. 430–433, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. A. E. Riek, J. Oh, and C. Bernal-Mizrachi, “1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients,” Journal of Steroid Biochemistry and Molecular Biology, vol. 136, pp. 309–312, 2013.
  117. F. Carbone, A. Nencioni, F. Mach, N. Vuilleumier, and F. Montecucco, “Pathophysiological role of neutrophils in acute myocardial infarction,” Thrombosis and Haemostasis, vol. 110, no. 3, pp. 501–514, 2013. View at Publisher · View at Google Scholar
  118. D. Hirsch, F. E. Archer, M. Joshi-Kale, A. M. Vetrano, and B. Weinberger, “Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils,” Mediators of Inflammation, vol. 2011, Article ID 598345, 7 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  119. K. Takahashi, Y. Nakayama, H. Horiuchi et al., “Human neutrophils express messenger RNA of vitamin D receptor and respond to 1α,25-dihydroxyvitamin D3,” Immunopharmacology and Immunotoxicology, vol. 24, no. 3, pp. 335–347, 2002. View at Publisher · View at Google Scholar · View at Scopus
  120. M. F. Lipscomb and B. J. Masten, “Dendritic cells: immune regulators in health and disease,” Physiological Reviews, vol. 82, no. 1, pp. 97–130, 2002. View at Scopus
  121. A. Niessner and C. M. Weyand, “Dendritic cells in atherosclerotic disease,” Clinical Immunology, vol. 134, no. 1, pp. 25–32, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. E. L. Gautier, T. Huby, F. Saint-Charles et al., “Conventional dendritic cells at the crossroads between immunity and cholesterol homeostasis in atherosclerosis,” Circulation, vol. 119, no. 17, pp. 2367–2375, 2009. View at Publisher · View at Google Scholar · View at Scopus
  123. C. Combadière, S. Potteaux, J. Gao et al., “Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice,” Circulation, vol. 107, no. 7, pp. 1009–1016, 2003. View at Publisher · View at Google Scholar · View at Scopus
  124. P. Liu, Y. A. Yu, J. A. Spencer et al., “CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 2, pp. 243–250, 2008. View at Publisher · View at Google Scholar · View at Scopus
  125. C. Combadière, S. Potteaux, M. Rodero et al., “Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice,” Circulation, vol. 117, no. 13, pp. 1649–1657, 2008. View at Publisher · View at Google Scholar · View at Scopus
  126. J. Fritsche, K. Mondal, A. Ehrnsperger, R. Andreesen, and M. Kreutz, “Regulation of 25-hydroxyvitamin D3-1α-hydroxylase and production of 1α,25-dihydroxyvitamin D3 by human dendritic cells,” Blood, vol. 102, no. 9, pp. 3314–3316, 2003. View at Publisher · View at Google Scholar · View at Scopus
  127. J. S. Adams, S. Ren, P. T. Liu et al., “Vitamin D-directed rheostatic regulation of monocyte antibacterial responses,” Journal of Immunology, vol. 182, no. 7, pp. 4289–4295, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. M. C. Gauzzi, C. Purificato, K. Donato et al., “Suppressive effect of 1α,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis,” Journal of Immunology, vol. 174, no. 1, pp. 270–276, 2005. View at Scopus
  129. C. Almerighi, A. Sinistro, A. Cavazza, C. Ciaprini, G. Rocchi, and A. Bergamini, “1α,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes,” Cytokine, vol. 45, no. 3, pp. 190–197, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. L. E. Bartels, C. L. Hvas, J. Agnholt, J. F. Dahlerup, and R. Agger, “Human dendritic cell antigen presentation and chemotaxis are inhibited by intrinsic 25-hydroxy vitamin D activation,” International Immunopharmacology, vol. 10, no. 8, pp. 922–928, 2010. View at Publisher · View at Google Scholar · View at Scopus
  131. K. Sochorová, V. Budinský, D. Rožková et al., “Paricalcitol (19-nor-1,25-dihydroxyvitamin D2) and calcitriol (1,25-dihydroxyvitamin D3) exert potent immunomodulatory effects on dendritic cells and inhibit induction of antigen-specific T cells,” Clinical Immunology, vol. 133, no. 1, pp. 69–77, 2009. View at Publisher · View at Google Scholar · View at Scopus
  132. M. Takeda, T. Yamashita, N. Sasaki et al., “Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory t cells and immature dendritic cells with tolerogenic functions,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 12, pp. 2495–2503, 2010. View at Publisher · View at Google Scholar · View at Scopus
  133. Y. V. Bobryshev, “Vitamin D3 suppresses immune reactions in atherosclerosis, affecting regulatory T cells and dendritic cell function,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 12, pp. 2317–2319, 2010. View at Publisher · View at Google Scholar · View at Scopus
  134. P. Libby, A. H. Lichtman, and G. K. Hansson, “Immune effector mechanisms implicated in atherosclerosis: from mice to humans,” Immunity, vol. 38, no. 6, pp. 1092–1104, 2013. View at Publisher · View at Google Scholar
  135. B. D. Mahon, A. Wittke, V. Weaver, and M. T. Cantorna, “The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells,” Journal of Cellular Biochemistry, vol. 89, no. 5, pp. 922–932, 2003. View at Publisher · View at Google Scholar · View at Scopus
  136. A. K. Yadav, D. Banerjee, A. Lal, and V. Jha, “Vitamin D deficiency, CD4+CD28null cells and accelerated atherosclerosis in chronic kidney disease,” Nephrology, vol. 17, no. 6, pp. 575–581, 2012. View at Publisher · View at Google Scholar
  137. G. Liuzzo, L. M. Biasucci, G. Trotta et al., “Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events,” Journal of the American College of Cardiology, vol. 50, no. 15, pp. 1450–1458, 2007. View at Publisher · View at Google Scholar · View at Scopus
  138. S. W. Kang, S. H. Kim, N. Lee et al., “1,25-dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region,” Journal of Immunology, vol. 188, no. 11, pp. 5276–5282, 2012. View at Publisher · View at Google Scholar
  139. E. S. Chambers, A. M. Nanzer, D. F. Richards et al., “Serum 25-dihydroxyvitamin D levels correlate with CD4(+)Foxp3(+) T-cell numbers in moderate/severe asthma,” The Journal of Allergy and Clinical Immunology, vol. 130, no. 2, pp. 542–544, 2012. View at Publisher · View at Google Scholar
  140. H. Maalmi, A. Berraies, E. Tangour et al., “The impact of vitamin D deficiency on immune T cells in asthmatic children: a case-control study,” Journal of Asthma and Allergy, vol. 5, pp. 11–19, 2012.
  141. U. C. Bang, L. Brandt, T. Benfield, and J. E. Jensen, “Changes in 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D are associated with maturation of regulatory T lymphocytes in patients with chronic pancreatitis: a randomized controlled trial,” Pancreas, vol. 41, no. 8, pp. 1213–1218, 2012. View at Publisher · View at Google Scholar
  142. J. Correale, M. C. Ysrraelit, and M. I. Gaitn, “Immunomodulatory effects of vitamin D in multiple sclerosis,” Brain, vol. 132, no. 5, pp. 1146–1160, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. L. E. Jeffery, A. M. Wood, O. S. Qureshi et al., “Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses,” Journal of Immunology, vol. 189, no. 11, pp. 5155–5164, 2012. View at Publisher · View at Google Scholar
  144. M. Sata and D. Fukuda, “Crucial role of renin-angiotensin system in the pathogenesis of atherosclerosis,” Journal of Medical Investigation, vol. 57, no. 1-2, pp. 12–25, 2010. View at Scopus
  145. F. Diet, R. E. Pratt, G. J. Berry, N. Momose, G. H. Gibbons, and V. J. Dzau, “Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease,” Circulation, vol. 94, no. 11, pp. 2756–2767, 1996. View at Scopus
  146. Y. C. Li, J. Kong, M. Wei, Z. Chen, S. Q. Liu, and L. Cao, “1,25-dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system,” Journal of Clinical Investigation, vol. 110, no. 2, pp. 229–238, 2002. View at Publisher · View at Google Scholar · View at Scopus
  147. W. Yuan, W. Pan, J. Kong et al., “1,25-Dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter,” The Journal of Biological Chemistry, vol. 282, no. 41, pp. 29821–29830, 2007. View at Publisher · View at Google Scholar · View at Scopus
  148. M. Ish-Shalom, J. Sack, M. Vechoropoulos et al., “Low-dose calcitriol decreases aortic renin, blood pressure, and atherosclerosis in apoe-null mice,” Journal of Atherosclerosis and Thrombosis, vol. 19, no. 5, pp. 422–434, 2012. View at Publisher · View at Google Scholar
  149. S. Weng, J. E. Sprague, J. Oh et al., “Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice,” PLoS ONE, vol. 8, no. 1, Article ID e54625, 2013. View at Publisher · View at Google Scholar
  150. J. H. Ix, R. Katz, B. R. Kestenbaum et al., “Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health study),” Journal of the American College of Cardiology, vol. 60, no. 3, pp. 200–207, 2012. View at Publisher · View at Google Scholar
  151. A. L. Negri, “Fibroblast growth factor 23: associations with cardiovascular disease and mortality in chronic kidney disease,” International Urology and Nephrology, 2013. View at Publisher · View at Google Scholar
  152. H. Masai, N. Joki, K. Sugi, and M. Moroi, “A preliminary study of the potential role of FGF-23 in coronary calcification in patients with suspected coronary artery disease,” Atherosclerosis, vol. 226, no. 1, pp. 228–233, 2013. View at Publisher · View at Google Scholar
  153. M. S. Razzaque, D. Sitara, T. Taguchi, R. St-Arnaud, and B. Lanske, “Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process,” The FASEB Journal, vol. 20, no. 6, pp. 720–722, 2006. View at Publisher · View at Google Scholar · View at Scopus
  154. P. Hu, Q. Xuan, B. Hu, L. Lu, J. Wang, and Y. H. Qin, “Fibroblast growth factor-23 helps explain the biphasic cardiovascular effects of vitamin D in chronic kidney disease,” International Journal of Biological Sciences, vol. 8, no. 5, pp. 663–671, 2012.
  155. M. J. Glade, “Vitamin D: health panacea or false prophet?” Nutrition, vol. 29, no. 1, pp. 37–41, 2013. View at Publisher · View at Google Scholar

PDF is attached at the bottom of this page

See also VitaminDWiki


8658 visitors, last modified 21 Feb, 2014,
Printer Friendly Follow this page for updates