Vitamin D represents a group of secosteroids involved in the calcium and phosphate metabolism. The active form of vitamin D, 1,25-dihydroxylcalciferol, exerts its biological mechanisms via the VDR which acts as a regulator of several target genes.
Vitamin D is a group of secosteroids that physiologically improve the intestinal absorption of calcium and phosphate. The most important compounds of the vitamin D group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) [1]. The first association between vitamin D and cardiovascular diseases was reported by Scragg et al. [2], who recognized a seasonality in people suffering from heart disease. In particular, winter was the season when heart diseases were more frequent, possibly due to low levels of vitamin D. Cholecalciferol and ergocalciferol can be taken with food. After food intake, vitamin D2 undergoes two distinct metabolic processes. Firstly, vitamin D2 is metabolized in the liver to 25-hydroxyvitamin D, which in the kidney is, subsequently, converted by the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) to its active form, named 25-dihydroxyvitamin D (calcitriol) [3]. The endocrine production of calcitriol is regulated by feedback mechanisms involving bone, calcium, and the phosphorus metabolism. Calcitriol production is stimulated by the parathyroid hormone (PTH), released upon the reduction in calcium plasma levels. Calcitriol in turn directly suppresses the PTH gene transcription and the consequent hormone production, thereby increasing serum calcium levels. Furthermore, calcitriol also upregulates gene transcription and protein expression of the calcium-sensing receptor. Moreover, vitamin D regulates its own production by inhibiting CYP27B1 [4]. Additionally, under exposure to sunlight, the skin can synthesize vitamin D, namely, cholecalciferol [5]. The amount of sunlight needed to satisfy the vitamin D requirements is dependent on several factors such as skin pigmentation, age, latitude, season of the year, or time of the day [6]. Several diseases can be associated with low vitamin D levels. Rickets has long been recognized as a consequence of vitamin D deficiency. Furthermore, low vitamin D levels can be associated with other chronic disorders, such as atherosclerosis, coronary heart disease, arterial hypertension, heart failure [7], type 2 diabetes mellitus [8], cancer [9], and immunological disease [10]. Even if a pathogenic link between vitamin D deficiency and these diseases was established, the results of randomized clinical trials (RCT) designed to prove the therapeutic role of vitamin D supplementation have been inconclusive to date. However, it should be pointed out that the involvement of the vitamin D system in the pathogenesis of cardiovascular diseases is quite intricate. Indeed, within this context, a relevant role is also played by the autocrine/paracrine pathways locally activated by vitamin D inside atherosclerotic plaques [11][12]. In particular, it has been shown that vitamin D receptor (VDR) expression in human carotid plaques correlates with a reduction in major adverse cardiovascular events (MACE) [12].
8. Potential Impact of Calcium and Phosphate on Cardiovascular RiskBecause vitamin D is a key factor in the regulation of calcium/phosphate absorption and metabolism, it is quite logical that a relevant association can occur between changes in the levels of these metabolites and the overall cardiovascular risk [62]. Indeed, several experimental and clinical studies suggest that calcium, phosphate, and vitamin D can play an important role in the pathogenesis of cardiovascular diseases. Since calcium, phosphate, and vitamin D are closely connected, they constitute a biological axis that should be considered with regard to all these three components and their reciprocal relationships.
However, their coordinated roles in the development and progression of cardiovascular disorders have not yet been clearly elucidated. In fact, within the very complex scenario of the global cardiovascular risk, rationally designed clinical trials have so far failed to shed light on the real consequences of calcium/phosphate/vitamin D deficiencies or supplementations [63].
9. ConclusionsVitamin D represents a group of secosteroids involved in the calcium and phosphate metabolism; an adequate food intake and sunlight exposition are necessary to reach sufficient levels of vitamin D. Different diseases can be associated with low levels of vitamin D, that are not only related to bone and calcium metabolism diseases. Indeed, current evidence suggests a direct involvement of hypovitaminosis D in cardiovascular diseases. Both in vitro and in vivo animal models showed that vitamin D deficiency can cause or worsen endothelial dysfunction, favoring the onset and progression of atherosclerotic plaque.
Endothelial dysfunction and RAAS modulation have been shown to be implicated in the development of arterial hypertension due to vitamin D deficiency in animal reversible models, where the reintegration of vitamin D restored or improved the cardiovascular
impairment. Vitamin D deficiency in animal models is also related to heart hypertrophic remodeling, characterized by biochemical and echocardiographic changes similar to the
findings of the HFpEF. Even if the association between hypovitaminosis D and cardiovascular disease is well established in animal models, several trials and meta-analyses performed to prove eventual cardiovascular benefits of vitamin D supplementation in humans have been inconclusive, thereby never reaching significant results referring to MACE. Further studies are, thus, needed to eventually prove the supposed benefits of vitamin D supplementation.
References
1. Holick, M.F. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin. Proc. 2006, 81, 353–373. [CrossRef]
2. Scragg, R.; Jackson, R.; Holdaway, I.M.; Lim, T.; Beaglehole, R. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: A community-based study. Int. J. Epidemiol. 1990, 19, 559–563. [CrossRef]
3. Holick, M.F. Environmental factors that influence the cutaneous production of vitamin D. Am. J. Clin. Nutr. 1995, 61 (Suppl. 3), 638S–645S. [CrossRef]
4. Christakos, S.; Dhawan, P.; Verstuyf, A.; Verlinden, L.; Carmeliet, G. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol. Rev. 2016, 96, 365–408. [CrossRef]
5. Cashman, K.D.; Kiely, M. EURRECA-Estimating vitamin D requirements for deriving dietary reference values. Crit. Rev. Food Sci. Nutr. 2013, 53, 1097–1109. [CrossRef]
6. Terushkin, V.; Bender, A.; Psaty, E.L.; Engelsen, O.;Wang, S.Q.; Halpern, A.C. Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes. J. Am. Acad. Dermatol. 2010, 62, 929.e1–929.e9299. [CrossRef] [PubMed]
7. Wang, T.J. Vitamin D and Cardiovascular Disease. Annu. Rev. Med. 2016, 67, 261–272. [CrossRef] [PubMed]
8. Krul-Poel, Y.H.; TerWee, M.M.; Lips, P.; Simsek, S. Management of endocrine disease: The effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Eur. J. Endocrinol. 2017, 176, R1–R14. [CrossRef]
9. Fleet, J.C.; DeSmet, M.; Johnson, R.; Li, Y. Vitamin D and cancer: A review of molecular mechanisms. Biochem. J. 2012, 441, 61–76. [CrossRef] [PubMed]
10. Hewison, M. An update on vitamin D and human immunity. Clin. Endocrinol. 2012, 76, 315–325. [CrossRef] [PubMed]
11. Carbone, F.; Montecucco, F. The role of the intraplaque vitamin d system in atherogenesis. Scientifica (Cairo) 2013, 2013, 620504. [CrossRef]
12. Carbone, F.; Satta, N.; Burger, F.; Pagano, S.; Lescuyer, P.; Bertolotto, M.; Spinella, G.; Pane, B.; Palombo, D.; Pende, A.; et al. Vitamin D receptor is expressed within human carotid plaques and correlates with pro-inflammatory M1 macrophages. Vasc. Pharmacol. 2016, 85, 57–65. [CrossRef]
13. Bouillon, R.; Carmeliet, G.; Verlinden, L.; van Etten, E.; Verstuyf, A.; Luderer, H.F.; Lieben, L.; Mathieu, C.; Demay, M. Vitamin D and human health: Lessons from vitamin D receptor null mice. Endocr. Rev. 2008, 29, 726–776. [CrossRef] [PubMed]
14. Haussler, M.R.; Whitfield, G.K.; Kaneko, I.; Haussler, C.A.; Hsieh, D.; Hsieh, J.C.; Jurutka, P.W. Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 2013, 92, 77–98. [CrossRef] [PubMed]
15. Wang, Y.; DeLuca, H.F. Is the vitamin d receptor found in muscle? Endocrinology 2011, 152, 354–363. [CrossRef] [PubMed]
16. Li, Y.C.; Qiao, G.; Uskokovic, M.; Xiang,W.; Zheng,W.; Kong, J. Vitamin D: A negative endocrine regulator of the renin-angiotensin system and blood pressure. J. Steroid Biochem. Mol. Biol. 2004, 89–90, 387–392. [CrossRef] [PubMed]
17. Li, Y.C.; Kong, J.; Wei, M.; Chen, Z.F.; Liu, S.Q.; Cao, L.P. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Investig. 2002, 110, 229–238. [CrossRef]
18. Weishaar, R.E.; Simpson, R.U. Vitamin D3 and cardiovascular function in rats. J. Clin. Investig. 1987, 79, 1706–1712. [CrossRef]
19. Sciacqua, A.; Perticone, M.; Grillo, N.; Falbo, T.; Bencardino, G.; Angotti, E.; Arturi, F.; Parlato, G.; Sesti, G.; Perticone, F. Vitamin D and 1-hour post-load plasma glucose in hypertensive patients. Cardiovasc. Diabetol. 2014, 13, 48. [CrossRef]
20. Forman, J.P.; Scott, J.B.; Ng, K.; Drake, B.F.; Suarez, E.G.; Hayden, D.L.; Bennett, G.G.; Chandler, P.D.; Hollis, B.W.; Emmons, K.M.; et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 2013, 61, 779–785. [CrossRef]
21. Larsen, T.; Mose, F.H.; Bech, J.N.; Hansen, A.B.; Pedersen, E.B. Effect of cholecalciferol supplementation during winter months in patients with hypertension: A randomized, placebo-controlled trial. Am. J. Hypertens. 2012, 25, 1215–1222. [CrossRef] [PubMed]
22. Witham, M.D.; Nadir, M.A.; Struthers, A.D. Effect of vitamin D on blood pressure: A systematic review and meta-analysis. J. Hypertens. 2009, 27, 1948–1954. [CrossRef] [PubMed]
23. Legarth, C.; Grimm, D.;Wehland, M.; Bauer, J.; Krüger, M. The Impact of Vitamin D in the Treatment of Essential Hypertension. Int. J. Mol. Sci. 2018, 19, 455. [CrossRef]
24. Victor, V.M.; Rocha, M.; Solá, E.; Bañuls, C.; Garcia-Malpartida, K.; Hernández-Mijares, A. Oxidative stress, endothelial dysfunction and atherosclerosis. Curr. Pharm. Des. 2009, 15, 2988–3002. [CrossRef] [PubMed]
25. Zhang, Q.Y.; Jiang, C.M.; Sun, C.; Tang, T.F.; Jin, B.; Cao, D.W.; He, J.S.; Zhang, M. Hypovitaminosis D is associated with endothelial dysfunction in patients with non-dialysis chronic kidney disease. J. Nephrol. 2015, 28, 471–476. [CrossRef]
26. Napoli, C.; de Nigris, F.;Williams-Ignarro, S.; Pignalosa, O.; Sica, V.; Ignarro, L.J. Nitric oxide and atherosclerosis: An update. Nitric Oxide 2006, 15, 265–279. [CrossRef]
27. Zehnder, D.; Bland, R.; Chana, R.S.; Wheeler, D.C.; Howie, A.J.; Williams, M.C.; Stewart, P.M.; Hewison, M. Synthesis of 1,25-dihydroxyvitamin D3 by human endothelial cells is regulated by inflammatory cytokines: A novel autocrine determinant of vascular cell adhesion. J. Am. Soc. Nephrol. 2002, 13, 621–629. [CrossRef]
28. Cardús, A.; Parisi, E.; Gallego, C.; Aldea, M.; Fernández, E.; Valdivielso, J.M. 1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway. Kidney Int. 2006, 69, 1377–1384. [CrossRef]
29. Wu-Wong, J.R.; Nakane, M.; Ma, J.; Ruan, X.; Kroeger, P.E. Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 2006, 186, 20–28. [CrossRef]
30. Aihara, K.; Azuma, H.; Akaike, M.; Ikeda, Y.; Yamashita, M.; Sudo, T.; Hayashi, H.; Yamada, Y.; Endoh, F.; Fujimura, M.; et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J. Biol. Chem. 2004, 279, 35798–35802. [CrossRef]
31. Adams, J.S.; Ren, S.; Liu, P.T.; Chun, R.F.; Lagishetty, V.; Gombart, A.F.; Borregaard, N.; Modlin, R.L.; Hewison, M. Vitamin d-directed rheostatic regulation of monocyte antibacterial responses. J. Immunol. 2009, 182, 4289–4295. [CrossRef]
32. Quinn, C.M.; Jessup, W.;Wong, J.; Kritharides, L.; Brown, A.J. Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: A role for RXR and PPARgamma ligands. Biochem. J. 2005, 385 Pt 3, 823–830. [CrossRef]
33. Dickie, L.J.; Church, L.D.; Coulthard, L.R.; Mathews, R.J.; Emery, P.; McDermott, M.F. Vitamin D3 down-regulates intracellular Toll-like receptor 9 expression and Toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatology (Oxford) 2010, 49, 1466–1471. [CrossRef] [PubMed]
34. Liu, P.T.; Stenger, S.; Li, H.; Wenzel, L.; Tan, B.H.; Krutzik, S.R.; Ochoa, M.T.; Schauber, J.; Wu, K.; Meinken, C.; et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311, 1770–1773. [CrossRef] [PubMed]
35. Chen, S.; Sims, G.P.; Chen, X.X.; Gu, Y.Y.; Chen, S.; Lipsky, P.E. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 2007, 179, 1634–1647. [CrossRef] [PubMed]
36. Boonstra, A.; Barrat, F.J.; Crain, C.; Heath, V.L.; Savelkoul, H.F.; O’Garra, A. 1 ,25-Dihydroxyvitamin D3 has a direct effect on naive CD4+ T cells to enhance the development of Th2 cells. J. Immunol. 2001, 167, 4974–4980. [CrossRef] [PubMed]
37. Oh, J.;Weng, S.; Felton, S.K.; Bhandare, S.; Riek, A.; Butler, B.; Proctor, B.M.; Petty, M.; Chen, Z.; Schechtman, K.B.; et al. 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation 2009, 120, 687–698. [CrossRef]
38. Yin, K.; You, Y.; Swier, V.; Tang, L.; Radwan, M.M.; Pandya, A.N.; Agrawal, D.K. Vitamin D Protects against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 2432–2442. [CrossRef]
39. Chen, S.; Swier, V.J.; Boosani, C.S.; Radwan, M.M.; Agrawal, D.K. Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 1651–1659. [CrossRef]
40. Kasuga, H.; Hosogane, N.; Matsuoka, K.; Mori, I.; Sakura, Y.; Shimakawa, K.; Shinki, T.; Suda, T.; Taketomi, S. Characterization of transgenic rats constitutively expressing vitamin D-24-hydroxylase gene. Biochem. Biophys. Res. Commun. 2002, 297, 1332–1338. [CrossRef]
41. Neeland, I.J.; Poirier, P.; Després, J.P. Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management. Circulation 2018, 137, 1391–1406. [CrossRef]
42. Hyppönen, E.; Boucher, B.J. Adiposity, vitamin D requirements, and clinical implications for obesity-related metabolic abnormalities. Nutr. Rev. 2018, 76, 678–692. [CrossRef] [PubMed]
43. Bodyak, N.; Ayus, J.C.; Achinger, S.; Shivalingappa, V.; Ke, Q.; Chen, Y.S.; Rigor, D.L.; Stillman, I.; Tamez, H.; Kroeger, P.E.; et al. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc.Natl. Acad. Sci. USA 2007, 104, 16810–16815. [CrossRef] [PubMed]
44. Meems, L.M.; Cannon, M.V.; Mahmud, H.; Voors, A.A.; van Gilst, W.H.; Silljé, H.H.; Ruifrok, W.P.; de Boer, R.A. The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload. J. Steroid Biochem. Mol. Biol. 2012, 132, 282–289. [CrossRef] [PubMed]
45. Green, J.J.; Robinson, D.A.; Wilson, G.E.; Simpson, R.U.; Westfall, M.V. Calcitriol modulation of cardiac contractile performance via protein kinase C. J. Mol. Cell. Cardiol. 2006, 41, 350–359. [CrossRef] [PubMed]
46. Walters, M.R.; Ilenchuk, T.T.; Claycomb, W.C. 1,25-Dihydroxyvitamin D3 stimulates 45Ca2+ uptake by cultured adult rat ventricular cardiac muscle cells. J. Biol. Chem. 1987, 262, 2536–2541. [CrossRef]
47. Weishaar, R.E.; Kim, S.N.; Saunders, D.E.; Simpson, R.U. Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties. Am. J. Physiol. 1990, 258 Pt 1, E134–E142. [CrossRef] [PubMed]
48. Chen, S.; Law, C.S.; Grigsby, C.L.; Olsen, K.; Hong, T.T.; Zhang, Y.; Yeghiazarians, Y.; Gardner, D.G. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 2011, 124, 1838–1847. [CrossRef]
49. Magurno, M.; Crescibene, D.; Spinali, M.; Cassano, V.; Armentaro, G.; Barbara, K.; Miceli, S.; Hribal, M.L.; Perticone, M.; Sciacqua, A. Vitamin D and Subclinical Cardiovascular Damage in Essential Hypertension. Endocrines 2021, 2, 13. [CrossRef]
50. Rahman, A.; Hershey, S.; Ahmed, S.; Nibbelink, K.; Simpson, R.U. Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. J. Steroid Biochem. Mol. Biol. 2007, 103, 416–419. [CrossRef]
51. Manson, J.E.; Cook, N.R.; Lee, I.M.; Christen,W.; Bassuk, S.S.; Mora, S.; Gibson, H.; Gordon, D.; Copeland, T.; D’Agostino, D.; et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N. Engl. J. Med. 2019, 380, 33–44. [CrossRef]
52. Hsia, J.; Heiss, G.; Ren, H.; Allison, M.; Dolan, N.C.; Greenland, P.; Heckbert, S.R.; Johnson, K.C.; Manson, J.E.; Sidney, S.; et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007, 115, 846–854. [CrossRef]
53. Dalan, R.; Liew, H.; Assam, P.N.; Chan, E.S.; Siddiqui, F.J.; Tan, A.W.; Chew, D.E.; Boehm, B.O.; Leow, M.K. A randomised controlled trial evaluating the impact of targeted vitamin D supplementation on endothelial function in type 2 diabetes mellitus: The DIMENSION trial. Diabetes Vasc. Dis. Res. 2016, 13, 192–200. [CrossRef]
54. Aslanabadi, N.; Jafaripor, I.; Sadeghi, S.; Hamishehkar, H.; Ghaffari, S.; Toluey, M.; Azizi, H.; Entezari-Maleki, T. Effect of Vitamin D in the Prevention of Myocardial Injury Following Elective Percutaneous Coronary Intervention: A Pilot Randomized Clinical Trial. J. Clin. Pharmacol. 2018, 58, 144–151. [CrossRef]
55. Hin, H.; Tomson, J.; Newman, C.; Kurien, R.; Lay, M.; Cox, J.; Sayer, J.; Hill, M.; Emberson, J.; Armitage, J.; et al. Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care. Osteoporos. Int. 2017, 28, 841–851. [CrossRef] [PubMed]
56. Neale, R.E.; Armstrong, B.K.; Baxter, C.; Duarte Romero, B.; Ebeling, P.; English, D.R.; Kimlin, M.G.; McLeod, D.S.; O’Connell, R.L.; van der Pols, J.C.; et al. The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer. Contemp. Clin. Trials 2016, 48, 83–90. [CrossRef]
57. Legarth, C.; Grimm, D.; Krüger, M.; Infanger, M.; Wehland, M. Potential Beneficial Effects of Vitamin D in Coronary Artery Disease. Nutrients 2019, 12, 99. [CrossRef] [PubMed]
58. Seibert, E.; Lehmann, U.; Riedel, A.; Ulrich, C.; Hirche, F.; Brandsch, C.; Dierkes, J.; Girndt, M.; Stangl, G.I. Vitamin D3 supplementation does not modify cardiovascular risk profile of adults with inadequate vitamin D status. Eur. J. Nutr. 2017, 56, 621–634. [CrossRef] [PubMed]
59. Gholami, F.; Moradi, G.; Zareei, B.; Rasouli, M.A.; Nikkhoo, B.; Roshani, D.; Ghaderi, E. The association between circulating 25-hydroxyvitamin D and cardiovascular diseases: A meta-analysis of prospective cohort studies. BMC Cardiovasc. Disord. 2019, 19, 248. [CrossRef]
60. Barbarawi, M.; Kheiri, B.; Zayed, Y.; Barbarawi, O.; Dhillon, H.; Swaid, B.; Yelangi, A.; Sundus, S.; Bachuwa, G.; Alkotob, M.L.; et al. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83,000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. JAMA Cardiol. 2019, 4, 765–776. [CrossRef]
61. De la Guía-Galipienso, F.; Martínez-Ferran, M.; Vallecillo, N.; Lavie, C.J.; Sanchis-Gomar, F.; Pareja-Galeano, H. Vitamin D and cardiovascular health. Clin. Nutr. 2021, 40, 2946–2957. [CrossRef]
62. Brown, R.B.; Haq, A.; Stanford, C.F.; Razzaque, M.S. Vitamin D, phosphate, and vasculotoxicity. Can. J. Physiol. Pharmacol. 2015,93, 1077–1082. [CrossRef]
63. Heine, G.H.; Nangaku, M.; Fliser, D. Calcium and phosphate impact cardiovascular risk. Eur. Heart J. 2013, 34, 1112–1121.