Role of Vitamin D in Cardiovascular Diseases

Abstract

Vitamin D is critical in mineral homeostasis and skeletal health and plays a regulatory role in nonskeletal tissues. Vitamin D deficiency is associated with chronic inflammatory diseases, including diabetes and obesity, both strong risk factors for cardiovascular diseases (CVDs). CVDs, including coronary artery disease, myocardial infarction, hypertrophy, cardiomyopathy, cardiac fibrosis, heart failure, aneurysm, peripheral arterial disease, hypertension, and atherosclerosis, are major causes of morbidity and mortality. The association of these diseases with vitamin D deficiency and improvement with vitamin D supplementation suggest its therapeutic benefit. The authors review the findings on the association of vitamin D deficiency and CVDs.

Keywords: Atherosclerosis; Cardiac failure and fibrosis; Cardiomyopathy; Cardiovascular disease; Left ventricular hypertrophy; Myocardial infarction; Peripheral vascular disease; Vitamin D deficiency.

Figure 1. Schematic representation for synthesis and regulation of vitamin D

Dietary vitamin D (vitamin D) and pro-vitamin D synthesized in skin under UV light reaches the liver via the blood stream after binding with vitamin D binding protein (VDBP). Hydroxylation of vitamin D mainly with Cyp2R1 (vitamin D 25 hydroxylase) results in the formation of calcidiol (25(OH)D) which is further hydroxylated with Cyp27B1 (1 α-hydroxylase) in the kidney to form calcitriol (1,25(OH)₂D₃)-the biologically active form of vitamin D. The activity of Cyp27B1 is regulated by the plasma levels of calcium, phosphate, parathyroid hormone (PTH), fibroblast growth factor-23 (FGF23) and 1,25(OH)₂D₃ itself. RXRα-retinoid X receptor-α, VDR-vitamin D receptor, VDRE-vitamin D response elements.

Figure 2. Role of vitamin D deficiency in the pathogenesis of cardiovascular diseases

Vitamin D (vitamin D) deficiency is associated with many diseases such as diabetes, obesity, metabolic syndrome, hypercholesterolemia, and hypoparathyroidism, and CVD (cardiovascular disease/s). Vitamin D deficiency results in increased inflammation, increased expression of inflammatory cytokines, and decreased expression and activity of VDR (vitamin D receptor). This results in enhanced signaling of downstream inflammatory signaling cascades leading to collagen loss, fibrosis, increased oxidative stress, increased inflammation, increased sensitivity to infections, and decreased protective mechanisms. The cumulative effect of this results in various CVD such as cardiomyopathy, hypertrophy, myocardial infarction, heart failure, cardiac fibrosis, and rhythm abnormalities. Hence, vitamin D supplementation might decrease these mediators and attenuate the progression and development of CVD. AT1R- angiotensin II type 1 receptor, CTGF- connective tissue growth factor, col 1-collagen 1, col 3- collagen 3, EMT-epithelial- myofibroblast transformation, EndMT-endothelial myofibroblast transformation, ERK1/2- protein-serine/threonine kinases, HDL- high-density lipoprotein, IKBα-α subunit of inhibitor of κB, IL-6 – interleukin-6, IL-1β – interleukin-1 beta, IL-33 – interleukin-33, IFN-γ-interferon-gamma, LDL-low-density lipoprotein, MMPs - matrix metalloproteinases, mTOR-mechanistic target of rapamycin, NF-κB- nuclear-factor kappa beta, PARP1- poly [ADP-ribose] polymerase 1, RAGEreceptor for advanced glycation end products, RAS-renin-angiotensin system, RAAS- renin-angiotensin-aldosterone system, SIRT1-sirtuin1, SMAD2/3 - Sma- and Mad-Related Protein 2/3, TG- triglycerides, TCtotal cholesterol, TIMPs- tissue inhibitors of metalloproteinases, TNF-α-tumor necrosis factor-alpha, TGF-β1- transforming growth factor-beta 1, VDR-vitamin D receptor, vitamin D-vitamin D

Figure 3. Vitamin D deficiency and development of vascular diseases

Vitamin D deficiency is associated with increased inflammation, increased expression of inflammatory cytokines, endothelial cell and vascular smooth muscle cells dysfunction, and decreased expression and activity of VDR. This enhances and aids in the development of vascular diseases such as atherosclerosis, aneurysms, calcification, stiffness, and hypertension. Since vitamin D deficiency is associated with the pathogenesis of development and progression of vascular diseases, vitamin D supplementation might help in attenuating the development and progression of these vascular diseases. CCL2- chemokine (C-C motif) ligand 2, CCL5- chemokine (C-C motif) ligand 5, CXCL1- Chemokine (C-X-C Motif) Ligand 1, EC- endothelial cells, ERK1/2- protein-serine/threonine kinases, HIF-1 α-hypoxia-induced factor-1 alpha, HTN- hypertension, IL-2,IL-4, IL-6, IL-10 – interleukin-2, interleukin-4, interluekin-6, interleukin-10, IL-1β – interleukin-1 beta, IFN-γ-interferon-gamma, MMP2 and MMP9 - matrix metalloproteinases 2 and 9, p38MAPKp38 mitogen-activated protein kinases, pNF-κB- phosphorylated nuclear-factor kappa beta, PAR-2- protease-activated protein 2, PVAT- perivascular adipose tissue, RAS- renin-angiotensin system, TREM-1-triggering receptor expressed on myeloid cells 1, TLR2- toll-like receptor 2, TLR4- toll-like receptor 4, TNF-α-tumor necrosis factor-alpha, VSMC-TF- vascular smooth muscle cells-tissue factor, VDR-vitamin D receptor, vitamin D-vitamin D.