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 thereafter89.  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 (P<0.05)14.  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 atherosclerosis1819.

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

References

  1. Zittermann, A. Schleithoff, S. S. Koerfer, R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005 Oct; 94 (4): 483-92.
  2. Chen, S. Law, C. S. Gardner, D. G. Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity. J Steroid Biochem Mol Biol. 2010 Feb 15; 118 (3): 135-41.
  3. Johnson, R. C. Leopold, J. A. Loscalzo, J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res. 2006 Nov 10; 99 (10): 1044-59.
  4. London, G. M. Guerin, A. P. Verbeke, F. H. Pannier, B. Boutouyrie, P. Marchais, S. J. Metivier, F. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007 Feb; 18 (2): 613-20.
  5. Mizobuchi, M. Ogata, H. Koiwa, F. Kinugasa, E. Akizawa, T. Vitamin D and vascular calcification in chronic kidney disease. Bone. 2009 Jul; 45 Suppl 1S26-9.
  6. Takasu, H. Anti-osteoclastogenic action of active vitamin D. Nutr Rev. 2008 Oct; 66 (10 Suppl 2): S113-5.
  7. Dusso, A. Arcidiacono, M. V. Yang, J. Tokumoto, M. Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol. 2010 Jul; 121 (1-2): 193-8.
  8. Lappe J M et al Vitamin D status in a rural postmenopausal female population. J Am Coll Nutr. 2006 Oct; 25 (5): 395-402.
  9. Okazaki R et al Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D(3) load in Japanese subjects. J Bone Miner Metab. 2010 Jun; 22
  10. Walker, M. D. et al. Carotid vascular abnormalities in primary hyperparathyroidism. J Clin Endocrinol Metab. 2009 Oct; 94 (10): 3849-56.
  11. Snijder, M. B. et al Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med. 2007 Jun; 261 (6): 558-65.
  12. Hypponen, E. Boucher, B. J. Berry, D. J. Power, C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes. 2008 Feb; 57 (2): 298-305.
  13. Lowe, G. D. Danesh, J. Lewington, S. Walker, M. Lennon, L. Thomson, A. Rumley, A. Whincup, P. H. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J. 2004 Feb; 25 (3): 252-9.
  14. Diaz, L et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol. 2009 Jul; 81 (8): 17-24.
  15. Timms, P. M. Mannan, N. Hitman, G. A. Noonan, K. Mills, P. G. Syndercombe-Court, D. Aganna, E. Price, C. P. Boucher, B. J. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?. QJM. 2002 Dec; 95 (12): 787-96.
  16. Derosa, G. D’Angelo, A. Scalise, F. Avanzini, M. A. Tinelli, C. Peros, E. Fogari, E. Cicero, A. F. Comparison between metalloproteinases-2 and -9 in healthy subjects, diabetics, and subjects with acute coronary syndrome. Heart Vessels. 2007 Nov; 22 (6): 361-70.
  17. Welsh, P. Whincup, P. H. Papacosta, O. Wannamethee, S. G. Lennon, L. Thomson, A. Rumley, A. Lowe, G. D. Serum matrix metalloproteinase-9 and coronary heart disease: a prospective study in middle-aged men. QJM. 2008 Oct; 101 (10): 785-91.
  18. Laxton, R. C. Hu, Y. Duchene, J. Zhang, F. Zhang, Z. Leung, K. Y. Xiao, Q. Scotland, R. S. Hodgkinson, C. P. Smith, K. Willeit, J. Lopez-Otin, C. Simpson, I. A. Kiechl, S. Ahluwalia, A. Xu, Q. Ye, S. A role of matrix metalloproteinase-8 in atherosclerosis. Circ Res. 2009 Oct 23; 105 (9): 921-9.
  19. Mallat, Z. Matrix metalloproteinase-8 and the regulation of blood pressure, vascular inflammation, and atherosclerotic lesion growth. Circ Res. 2009 Oct 23; 105 (9): 827-9.
  20. Alsafwah, S. Laguardia, S. P. Arroyo, M. Dockery, B. K. Bhattacharya, S. K. Ahokas, R. A. Newman, K. P. Congestive heart failure is a systemic illness: a role for minerals and micronutrients. Clin Med Res. 2007 Dec; 5 (4): 238-43.
  21. Gupta, R. Sharma, U. Gupta, N. Kalaivani, M. Singh, U. Guleria, R. Jagannathan, N. R. Goswami, R. Effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in vitamin D deficient Asian Indians: A randomized controlled trial. Clin Endocrinol (Oxf). 2010 Apr 23;
  22. Visvanathan, R. Chapman, I. Preventing sarcopaenia in older people. Maturitas. 2010 Aug; 66 (4): 383-8.
  23. Schubert, L. DeLuca, H. F. Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency. Arch Biochem Biophys. 2010 Aug 15; 500 (2): 157-61.
  24. Weber, K. T. Weglicki, W. B. Simpson, R. U. Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium. Cardiovasc Res. 2009 Feb 15; 81 (3): 500-8.