Potential for vitamin D receptor agonists in the treatment of cardiovascular disease

Abstract

Vitamin D(3) is made in the skin and modified in the liver and kidney to form the active metabolite, 1,25-dihydroxyvitamin D(3) (calcitriol). Calcitriol binds to a nuclear receptor, the vitamin D receptor (VDR), and activates VDR to recruit cofactors to form a transcriptional complex that binds to vitamin D response elements in the promoter region of target genes. During the past three decades the field has focused mainly on the role of VDR in the regulation of parathyroid hormone, intestinal calcium/phosphate absorption and bone metabolism; several VDR agonists (VDRAs) have been developed for the treatment of osteoporosis, psoriasis and hyperparathyroidism secondary to chronic kidney disease (CKD). Emerging evidence suggests that VDR plays important roles in modulating cardiovascular, immunological, metabolic and other functions. For example, data from epidemiological, preclinical and clinical studies have shown that vitamin D and/or 25(OH)D deficiency is associated with increased risk for cardiovascular disease (CVD). However, VDRA therapy seems more effective than native vitamin D supplementation in modulating CVD risk factors. In CKD, where decreasing VDR activation persists over the course of the disease and a majority of the patients die of CVD, VDRA therapy was found to provide a survival benefit in both pre-dialysis and dialysis CKD patients. Although VDR plays an important role in regulating cardiovascular function and VDRAs may be potentially useful for treating CVD, at present no VDRA is approved for CVD, and also no serum markers, beside parathyroid hormone in CKD, exist to indicate the efficacy of VDRA in CVD.

Figure 1

Vitamin D₃ is converted to 25-hydroxyvitamin D₃ (25(OH)D₃) in the liver, and then converted to the active metabolite, 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃ or calcitriol), by 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) in either renal or extra-renal tissues. Calcitriol binds to and activates vitamin D receptor (VDR) to regulate the expression of target genes. Calcitriol is metabolized by 25-hydroxyvitamin D-24-hydroxylase (24-OHase, CYP24) into excreted metabolites and also down-regulates CYP27B1 via a feedback mechanism. VDR is present in more than 30 tissues and may be involved in modulating diverse biological effects.

Figure 2

The structures and characteristics of some of the vitamin D analogs currently used to treat osteoporosis, psoriasis and hyperparathyroidism secondary to chronic kidney disease (CKD) (SHPT).

Figure 3

Effect of calcitriol, paricalcitol and 25-OH-doxercalciferol on renin suppression. As 4.1 cells were transfected with human vitamin D receptor cDNA-pcDNA3. After overnight incubation, cells were treated with paricalcitol, calcitriol or 25-OH-doxercalciferol at indicated concentrations for 24 h. Sample analysis was as described previously (Nakane et al., 2007). Statistical comparisons were performed by one-way anova, Dunnett's t-test.

Figure 4

Effects of paricalcitol and calcitriol on the expression of thrombomodulin (TM) and plasminogen activator inhibitor-1 (PAI-1) in human aortic smooth muscle cells. (A) and (C): Primary culture of human aortic smooth muscle cells were treated with paricalcitol or calcitriol at indicated concentrations for 24 h. RNA were isolated and the mRNA level of the genes analysed by real-time RT-PCR. (B) and (D): For Western blotting, cells were treated with paricalcitol or calcitriol at indicated concentrations for 48 h, and samples were analysed with a mouse anti-plasminogen activator inhibitor-1 (PAI-1) monoclonal antibody (1000-fold dilution, Santa Cruz Biotechnology, Santa Cruz, CA) or a mouse anti-thrombomodulin (TM) monoclonal antibody (2000-fold dilution, Santa Cruz Biotechnology) as described previously (Wu-Wong et al., 2007).

Figure 5

Effects of vitamin D receptor (VDR) activation in the blood vessel. VDR activation results in regulation of genes involved in the cell cycle that leads to inhibition of proliferation and induction of differentiation. BNP (natriuretic peptide B) is down-regulated. Regulation of genes such as thrombomodulin, plasminogen activator inhibitor-1 and thrombospondin-1 by VDRAs (VDR agonists or activators) results in reduced thrombogenicity and increased fibrinolysis. The regulation of type B endothelin receptor, oxytocin receptor and prostaglandin–endoperoxide synthase-1 suggest that VDRAs may also play roles in vessel relaxation and endothelial regeneration. Adapted from Wu-Wong et al. (2006a).

Figure 6

Differential effects of VDRAs (vitamin D receptor agonists or activators) on aortic calcification and pulse wave velocity (PWV). (A) Aortic calcium content in 5/6 nephrectomized uremic rats with hyperphosphatemia treated with vehicle, paricalcitol or doxercalciferol (0.17 µg·kg⁻¹, i.p. three times per week for 6 weeks). Adapted from Wu-Wong et al. (2006b). (B) Aortic PWV in 5/6 nephrectomized (NX) uremic rats with hyperphosphatemia treated with vehicle, paricalcitol or doxercalciferol (0.083, 0.167 and 0.333 µg·kg⁻¹, i.p. three times per week for 6 weeks). Data are from Noonan et al. (2008). * p < 0.05 vs own group, Day-1, ** p < 0.01 vs sham.

Figure 7

Echocardiogram parameters in haemodialysis patients. Changes in E/A ratio (A), left ventricular (LV) septal thickness (B), posterior wall (PW) thickness (C) and ejection fraction (D) in patients with (n= 15) and without (n= 6) paricalcitol (PC) treatment (average dose: 13 ± 7 µg·week⁻¹; duration of treatment: 4.3 ± 1.2 months). Data are from Bodyak et al. (2007).