An introduction to Cardiovascular diseasesHow does vitamin D work?

There are a number of mechanisms whereby vitamin D could reduce the risk of CVD.  These mechanisms include the inhibition of vascular smooth muscle proliferation, the suppression of vascular calcification, reduction of inflammation, and reduction of blood pressure1. Each is discussed briefly:

Inhibition of vascular smooth muscle proliferation

The hormonal metabolite of vitamin D, 1,25-dihyroxyvitamin D (calcitriol) inhibits endothelin (ET)-dependent DNA synthesis and cell proliferation by suppressing ET-induced activation of cyclin-dependent kinase 2 (Cdk2), a key cell cycle kinase2.

Suppression of vascular calcification

Vascular calcification is a consequence of tightly regulated processes that culminate in organized extracellular matrix deposition by osteoblast-like cells. Several factors induce this transition, including bone morphogenetic proteins, oxidant stress, high phosphate levels, parathyroid hormone fragments, and vitamin D3.

When the vascular walls become calcified (medial calcification), they lose elasticity and, as a result, contribute to increased blood pressure.  Medial calcification is associated with proliferation of vascular smooth muscle cells4.  

Vascular calcification can be affected by vitamin D receptors (VDRs), which affect gene activation.  When 25(OH)D and calcitriol levels are low, not enough VDRs can be activated to inhibit calcification.  The benefit of vitamin D is likely due to its activation of the VDR in vasculature and cardiac myocytes5.  One of the effects of calcitriol is to act upon osteoclast precursor cells and suppresses their differentiation in addition to intestinal and renal regulation of calcium and phosphorus6.

Vitamin D suppresses vascular calcification primarily by regulating parathyroid hormone (PTH).  High PTH causes mineral and skeletal abnormalities predisposing to ectopic calcifications and increased mortality7.  PTH levels decline fairly rapidly with increasing serum 25(OH)D levels to about 75 nmol/L, with little change thereafter8 9.  There are various lines of evidence that elevated PTH levels are linked to increased risk of vascular problems and dementia.  For example, in primary hyperparathyroidism (PHPT), PTH levels, but not calcium concentration, predicted carotid stiffness (P = 0.04), strain (P = 0.06), and distensibility (P = 0.07). Patients with increased carotid stiffness had significantly higher PTH levels than did those with normal stiffness (141 +/- 48 vs. 94.9 +/- 44 pg/ml, P = 0.002), and odds of abnormal stiffness increased 1.91 (confidence interval = 1.09-3.35; P = 0.024) for every 10 pg/ml increase in PTH, adjusted for age, creatinine, and albumin-corrected calcium10. A study in the Netherlands found that parathyroid hormone (PTH) levels were directly correlated with blood pressure, but serum 25(OH)D was not11 .  

Reduction of inflammation 

Vitamin D regulates inflammation in several ways.  

An observational study in England found a statistically significant inverse correlation between serum 25(OH)D and tissue plasminogen activator (tPA) antigen, with tPA levels peaking in August12.  (tPA is a protein involved in the breakdown of blood clots. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat only embolic or thrombotic stroke.)  tPA antigen was found to be associated with incidence of coronary heart disease13.

In a study of the effects of calcitriol on synthesis of mitochondrial RNAs encoding interleukin-6 (IL-6), interferon-gamma (IFN-gamma) in trophoblasts challenged with TNF-alpha found calcitriol inhibited the expression profile of inflammatory cytokine genes in a dose-response manner (P14.  Further findings regarding calcitriol and TNF-alpha are given in Dusso et al7.

Another way 25(OH)D reduces risk of CVD is through reduction in matrix metalloproteinases (MMPs) such as MMP915.  MMPs are a class of enzymes that can break down proteins, such as collagen and gelatin, and, thus, damage tissues in the vascular system.  MMP-2, MMP-9, TIMP-1, and TIMP-2 plasma levels were higher in diabetic, ACS, and DACS patients, which may reflect abnormal extracellular matrix metabolism in diabetes and in acute coronary syndrome16.  Serum MMP-9 has a modest association with incident CHD in the general population, which is not independent of cigarette smoking exposure and circulating markers of generalized inflammation. MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still play a role in the pathogenesis of CHD17. MMP-8 also plays a role in atherosclerosis18 19.

Reduction of blood pressure

Hypertension is a risk factor for CVD. See the document on hypertension for evidence that vitamin D reduces the risk of hypertension.

Muscle function

Muscle wasting is a characteristic of congestive heart failure20. There is growing evidence that vitamin D helps maintain muscle mass and strength21 and avoid sarcopenia (lack of muscle mass)22.  The mechanism seems to be avoidance of hypophosphatemia related to vitamin D deficiency23.  Vitamin D also protects the myocardium, which protect against heart failure or arrhythmias24.

Page last edited: 04 May 2011


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