Cardiovascular and metabolic effects of vitamin D

Abstract

In humans, approximately 95% of the total requirement for vitamin D is synthesized in the skin by the effects of sunlight. The active vitamin D synthesis from 25 (OH) D takes place via the 1-alpha hydroxylase enzyme both in renal and non-renal tissues. The effect of vitamin D on the receptor level is through active vitamin D. Vitamin D receptors are shown in more than 30 tissues. Non-classical effects of vitamin D are grouped under three main headings: Regulation of hormone secretion, regulation of immune function, regulation of cell proliferation and differentiation. Cardiovascular diseases, renal diseases, diabetes, obesity, metabolic syndrome are mostly researched diseases related with vitamin D. Vitamin D levels were shown inversely to be related with hypertension, obesity, diabetes and hypertriglyceridemia. In vitro studies have shown that vitamin D accelerates relaxation in cardiomyocytes and improves diastolic function of the heart. In clinical studies done in patients with chronic kidney disease, poor vitamin D status was shown to be an independent risk factor for coronary vascular calcification, other heart diseases such as heart failure, and cardiovascular mortality. In this review, the cardiovascular and metabolic effects of vitamin D have been reviewed in the light of current knowledge. J Clin Exp Invest 2013; 4 (3): 398-404

Keywords

• Vitamin D; cardiovascular system; diabetes mellitus; obesity; metabolic syndrome

D Vitamininin kardiyovasküler ve metabolik etkileri

Öz

İnsanlarda D vitamini ihtiyacının %95 kadarı güneş ışınlarının etkisiyle deride sentezlenmektedir. Böbrek dışı dokularda da 1-alfa hidroksilaz enzimi aracılığıyla 25(OH)D\'den aktif D vitamini sentezi gerçekleşmektedir. D vitamininin reseptör düzeyindeki etkisi aktif D vitamini sayesinde olur. D vitamini reseptörleri 30\'dan fazla dokuda gösterilmiştir. Vitamin D\'nin klasik olmayan etkileri 3 ana başlık altında toplanmaktadır: Hormon sekresyonunun regülasyonu, immün fonksiyonların regülasyonu, hücre proliferasyon ve farklılaşmasının düzenlenmesi. Kardiyovasküler hastalıklar, böbrek hastalıkları, diyabet, obezite, metabolik sendrom vitamin D ile ilişkisi en çok araştırılan hastalıklardır. Vitamin D düzeylerinin hipertansiyon, obezite, diyabet, hipertrigliseridemi ile ters ilişkili olduğu gösterilmiştir. İnvitro çalışmalarda aktif D vitamininin kardiyomiyositlerin relaksasyonunu hızlandırdığı ve kalbin diyastolik fonksiyonlarını iyileştirdiği gösterilmiştir. Kronik böbrek hastalığı olan hastalarda yapılan klinik çalışmalarda kötü vitamin D durumunun koroner vasküler kalsifikasyon, kalp yetmezliğini içeren kalp hastalıkları ve kardiyovasküler mortalite için bağımsız bir risk faktörü olduğu gösterilmiştir. Bu derlemede vitamin D\'nin kardiyovasküler ve metabolik etkileri güncel bilgiler ışığında gözden geçirilmiştir.

Anahtar Kelimeler

• D vitamini; kardiyovasküler sistem; diyabetes mellitus; obezite; metabolik sendrom

Kaynakça

1. Muszkat P, Camargo MB, Griz LH, Lazaretti-Castro M. Evidence-based non-skeletal actions of vitamin D. Arq Bras Endocrinol Metabol 2010;54:110-117.
2. Sözen T. D hormonu: Güncel gelişmeler. Hacettepe Tıp Dergisi 2011;42:14-27.
3. Özkan B, Döneray H. D vitamininin iskelet sistemi dışı etkileri. Çocuk Sağlığı ve Hastalıkları Dergisi 2011;54:99-119.
4. Nemere I, Carson F. Membrane receptors for steroid hormones: a case for spesific cell surface binding sites for vitamin D metabolites and estrogens. Bio- chem Biophys Res Com1998;248:442-449.
5. Norman AW. Receptors for 1,25(OH)2D3: past, pres- ent and future. J Bone Miner Res 1998;13:1360-1369.
6. De Luca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-2585.
7. Dawson-Hughes B, Heaney RP, Holick MF, Ips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713-716.
8. Bikle D. Nonclassic actions of Vitamin D. J Clin Endo- crinol Metab 2009;94:26-34.

9. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A sys- tematic review and meta-analysis. J Clin Endocrinol Metab 2007;92:2017-2029.
10. Ünal T, Özkan B, Çayır A, ve ark. Serum 25(OH) D vitamin düşüklüğü çocukluk çağı pnömonileri için bir risk faktörü müdür? Dicle Tıp Dergisi 2012;39:531- 535.
11. Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differen- tiation. J Immunol 2007;179:1634-1647.
12. Bikle DD, Oda Y, Xie Z. Calcium and 1,25(OH)2D: in- teracting drivers of epidermal differentiation. J Steroid Biochem Mol Biol 2004;89-90:355-360.
13. Holick MF. Vitamin D: extraskeletal health. Endocrinol Metab Clin North Am 2010;39:381-400.
14. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer - ready for prime time? (perspec- tive). N Engl J Med 2011;364:1385-1387.
15. Krishnan AV, Feldman D. Mechanisms of the antican- cer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 2011;51:311-336.
16. Deeb KK, Trump DL, Johnson CS. Vitamin D signaling pathways in cancer: potential for anticancer therapeu- tics. Nat Rev Cancer 2007;7:684-700.
17. Pilz S, Tomaschitz A, Drechsler C, de Boer RA. Vita- min D deficiency and heart disease. Kidney Interna- tional Supplements 2011;1:111-115.
18. Nibbelink KA, Tishkoff DX, Hershey SD, et al. 1,25(OH)2Vitamin D3 actions on cell proliferation, size, gene expression, and receptor localisation, in the HL-1 cardiac myocyte. J Steroid Biochem Mol Biol 2007;103:533-537.
19. O’Connell TD, Simpson RU. 1,25-dihydroxyvitamin D3 regulation of myocardial growth and c-myc lev- els in the rat heart. Biochem Biophys Res Commun 1995;213:59-65.
20. O’Connell TD, Berry JE, Jarvis AK, et al. 1,25-dihy- droxyvitamin D3 regulation of cardiac myocyte prolifer- ation and hypertrophy. Am J Physiol 1997;272:H1751- H1758.
21. Green JJ, Robinson DA, Wilson GE, et al. Calcitriol modulation of cardiac contractile performance via pro- tein kinase C. J Mol Cell Cardiol 2006;41:350-359.
22. De Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for re- duction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010;376:1543-1551.
23. Fleck A. Latitude and ischaemic heart disease. Lancet 1989:1:613.
24. Burgaz A, Orsini N, Larsson SC, et al. Blood 25-hy- droxyvitamin D concentration and hypertension: a meta-analysis. J Hypertens 2010;29:636-645.
25. Pittas AG, Chung M, Trikalinos T, et al. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 2010;152:307-314.
26. Pilz S, Tomaschitz A. Role of vitamin D in arterial hy- pertension. Expert Rev Cardiovasc Ther 2010;8:1599- 1608.
27. Brewer LC, Michos ED, Reis JP. Vitamin D in athero- sclerosis, vascular disease, and endothelial function. Curr Drug Targets 2011;12:54-60.
28. Garcia-Canton C, Bosch E, Ramirez A, et al. Vascular calcification and 25-hydroxyvitamin D levels in non- dialysis patients with chronic kidney disease stages 4 and 5. Nephrol Dial Transplant 2011;26:2250-2256.
29. Li X, Speer MY, Yang H, et al. Vitamin D receptor activators induce an anticalcific paracrine program in macrophages: requirement of osteopontin. Arterio- scler Thromb Vasc Biol 2010;30:321-326.
30. de Boer IH, Kestenbaum B, Shoben AB, et al. 25-hy- droxyvitamin D levels inversely associate with risk of developing coronary artery calcification. J Am Soc Nephrol 2009;20:1805-1812.
31. London GM, Guerin AP, Verbeke FH, et al. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D defi- ciency. J Am Soc Nephrol 2007;18:613-620.
32. Testa A, Mallamaci F, Benedetto FA, et al. Vitamin D receptor (VDR) gene polymorphism is associated with left ventricular (LV) mass and predicts left ven- tricular hypertrophy (LVH) progression in end-stage renal disease (ESRD) patients. J Bone Miner Res 2010;25:313-319.
33. Drechsler C, Pilz S, Obermayer-Pietsch B, et al. Vi- tamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J 2010;31:2253- 2261.
34. Rosen CJ, Adams JS, Bikle DD, et al. The Nonskel- etal effects of Vitamin D: an Endocrine Society Scien- tific Statement. Endocrine Reviews 2012;33:456-492.
35. Elamin MB, Abu Elnour NO, Elamin KB, et al. Vita- min D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011;96:1931-1942.
36. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D defi- ciency and risk of cardiovascular disease. Circulation 2008;117:503-511.
37. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25OHD and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008;168:1174-1180.
38. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25OHD and 1,25 D with all cause and cardiovascular mortality. Arch Intern Med 2008;168:1340-1349.
39. Martins D, Wolf M, Pan D. Prevalence of cardiovas- cular factors ad the serum levels of 25 hydroxyvitamin D in the United States: data from the third National Health and Nutrition Examination Surveys. Arch Intern Med 2007;167:1159-1165.
40. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized con- trolled trials. Arch Intern Med 2007;167:1730-1737.
41. Wang L, Manson JE, Song Y, et al. Systematic re- view: vitamin D and calcium supplementation in pre- vention of cardiovascular events. Ann Intern Med 2010;152:315-323.
42. Trivedi DP, Doll R, Khaw KT. Effect of four-monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469-473.
43. LaCroix AZ, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initia- tive calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci 2009;64:559-567.
44. Kandula P, Dobre M, Schold JD, et al. Vitamin D supplementation in chronic kidney disease: a system- atic review and meta-analysis of observational stud- ies and randomized controlled trials. Clin J Am Soc Nephrol 2011;6:50-62.
45. Matias PJ, Jorge C, Ferreira C, et al. Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimen- sion parameters. Clin J Am Soc Nephrol 2010;5:905- 911.
46. Kalantar-Zadeh K, Kovesdy CP. Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1529-1539.
47. Kim HW, Park CW, Shin YS, et al. Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract 2006;102:21-29.
48. Bodyak N, Ayus JC, Achinger S, et al. Activated vita- min D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci U S A 2007;104:16810-16815.
49. Bouillon R, Carmeliet G, Verlinden L, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 2008;29:726-776.
50. Wong KE, Szeto FL, Zhang W, et al. Involvement of the vitamin D receptor in energy metabolism regula- tion of uncoupling proteins. Am J Physiol Endocrinol Metab 2009; 296: E820-E828.
51. Narvaez CJ, Matthews D, Broun E, et al. Lean pheno- type and resistance to diet-induced obesity invitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocri- nology 2009;150:651-661.
52. Devaraj S, Jialal G, Cook T, et al. Low vitamin D levels in Northern American adults with the metabolic syn- drome. Horm Metab Res 2011;43:72-74.
53. Nunlee-Bland G, Gambhir K, Abrams C, et al. Vitamin D deficiency and insülin resistance in obese African- American adolescents. J Pediatr Endocrinol Metab 2011;24:29-33.
54. de Boer IH, Tinker LF, Connelly S, et al. Calcium plus vitamin D supplementation and the risk of incident dia- betes in the Women’s Health Initiative. Diabetes Care 2008;31:701-707.
55. von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient-a randomised, place- bo-controlled trial. Br J Nutr 2010;103:549-555.
56. Avenell A, Cook JA, MacLennan GS, McPherson GC. Vitamin D supplementation and type 2 diabetes: a substudy of a randomized placebo controlled trial in older people. Age Ageing 2009;38:606-609.
57. Jorde R, Sneve M, Emaus N, et al. Cross-sectional and longitudinal relation between serum 25-hydroxyvi- tamin D and body mass index: the Tromso study. Eur J Nutr 2010;49:401-407.