Vitamin D, a new antihypertensive hormone?
Recibido 30-ENE-2013 – ACEPTADO 07-FEBRERO-2013.
The authors declare not having a conflict of interest.
Humanityis facing apandemicof vitamin D deficiency that affectsn early 50% of the world population, which would bethe expression of a high pro inflammatory response of the population to cultural evolutionary changes. Low levels of Vitamin Dare associated with higher markers of inflammation and higher level sof RAS, causing hypertension, left ventricular hypertrophy, renal protectionfailure against hyperglycemia and atherosclerosis. Several controlled clinical trials and meta-analysis of randomized trials of supplementation with moderate and high doses of vitamin Dshowed mixed results in reducing mortality or cardiovascular riskin relation to vitamin D status. The effect of the drug pari calcitol, an activated form of vitamin D, on changes in the ratioof albumin/creatinine intype 2 diabetes and albuminuria (VITAL study) had no differences from placebo, but systolic blood pressure significantly reduced from 3 mmHgto 9 mmHg. For these reasons, it is not yet clear whet her vitamin D supplements may protect against cardiovascular disease, nor what would be the optimal serum levels to confer protection to individuals. Vitamin D is no tan antihypertensive drug, however, is likely to playa key role as regulating hormonein the cardiovascular system.
|Key words:Vitamin D. Hypertension. Atherosclerosis. Cardiovascular prevention..
Rev Fed Arg Cardiol. 2013; 42(1): 15-19
Since several years, the relation between serum levels of vitamin D (VitD) and blood pressure is known . Besides, there are plenty of papers by now showing that there is an increase in cardiovascular morbi-mortality, associated to low levels of VitD in serum .
On the other hand, the insufficiency of VitD affects almost 50% of the world population . This pandemic of hypovitaminosis D could be attributed mainly to the lifestyle(for example, by a reduction in outdoor activities), environmental (for example, by polluted air), and factors that reduce the exposition to sunlight (which is required to produce VitD in the skin by the action of ultraviolet-B radiation (UV-B)) .
However, it may be observed in literature that low levels of VitD are associated with higher inflammation markers . This makes us think that this pandemic of hypovitaminosis D would be the expression of a high pro-inflammatory response of the population before cultural evolutionary changes; changes that would also explain why cardiovascular disease is the number one cause of death in humans.
It is remarkable that all the conditions associated to a low production of VitD (by lack of UV-B induction), such a high latitude (greater distance from the equator), the industrialization and a dark skin, have also been associated to an increase in blood pressure values . Further, VitD deficiency has been related to myocardial infarction, stroke, and other cardiovascular diseases, including atherosclerosis and endothelial dysfunction .
Finally, more evidence is addedthat indicates that VitD plays a significant role in the regulation of the renin-angiotensin system (RAS), which could directly affect the cardiac muscle and the immunologic system regulation .
THE RELATION BETWEEN RAS AND VITAMIN D
Three decades ago, an original paper by Isakova et al, suggested a possible relation between VitD and RAS .
Recent studies have significantly improved our knowledge on the regulation of gene expression that encodes the production of renin on a cellular basis [9-11]. Some of these studies show that VitD could decrease the expression of the renin gene, and therefore, inhibit renin synthesis, thus suppressing RAS [12-15]. This finding is extremely interesting, in spite of the fact that the exact molecular mechanism has not been elucidated .
On the other hand, low VitD levels are associated to higher markers of inflammation and greater RAS levels, causing hypertension [14,16,17].
In animal models with VitD deficiency, a greater incidence of hypertension, left ventricular hypertrophy and atherosclerosis is observed . In normal mice, the deficiency of VitD stimulates the expression of renin, while the injection of VitD reduces the synthesis of renin. In cell cultures, VitD suppresses the transcription of the renin gene by a mechanism dependent on the vitamin D receptor (VDR). The mice that lack the VDR gene develop hyperreninemia, yielding as a result the high production of angiotensin II (AngII), which leads to hypertension, to cardiac hypertrophy, and the increase in the ingestion of water [13,18,19].
The higher levels of renin also may act through the prorenin/renin receptor  and may, regardless of AngII, cause renal and/or cardiovascular impairment . Recent studies show that diabetic mice with knockout for VDR developed a more severe nephropathy than wild mice, which suggests VitD protects from renal lesions caused by hyperglycemia by RAS regulation .
The inappropriate activation of RAS has been reported in knockout mice for VDR and 1α-hydroxylase [19,23]. These mice developed hypertension and myocardial hypertrophy, which continued present even after the normalization of the homeostasis of calcium; however, RAS block with angiotensin converter enzyme inhibitors (ACEI) normalized blood pressure and cardiac alterations [19,23]. On the other hand, the increase in RAS activation, hypertension and myocardial alterations may be treated successfully with VitD in knockout mice for 1α-hydroxylase .
Simpson et al, also showed that animals deficient in VitD had an increased incidence of hypertension, presented left ventricular hypertrophy and atherosclerosis .
The effect of VitD on renin is independent from calcium metabolism, the mechanisms of detection of salt volume or load, and the regulation of the AngII feedback [13,24]. Using a model of transgenic mice that overexpress human VDR, and working on renin-producing cells, Kong et al, showed that the suppression of the expression of renin by VitD in vivo is independent from the parathyroid hormone and calcium .
Recently, the molecular effects of VitD on RAS are more clear because of the discovery that the VDR ligand suppresses the transcription of the renin gene by blocking the AMPc activity in the promoting gene .
CLINICAL AND EPIDEMIOLOGICAL STUDIES
The clinical studies conducted over the last two decades have shown an inverse association between the plasma concentration of VitD and blood pressure and/or the activity of plasma renin, both in normotensive males and in patients with essential hypertension [1,26-28].
More recently, in a representative sample of the adult population, Sabanayagam et al, found that the lowest levels of serum VitD were associated with pre-hypertension, with a relative risk of 1.48 (CI 1.16-1.90) .
Other studies have shown a reduction in blood pressure in patients with primary hypertension that received VitD supplements [30,31], and a reduction in blood pressure, plasma renin, and the concentration of AngII in patients with secondary hyperparathyroidism [32,33].
Krause et al , made a study in which the participants were exposed to UV-B radiation in a solar bed 3 times a week for 3 months. The subjects experienced a 180% increase in their production of VitD and a reduction of 6 mmHg both in systolic and diastolic pressure. A small randomized, controlled against placebo study, carried out in patients with type 2 diabetes and with basal levels of VitD showed that a single dose of 100,000 UI of VitD reduces systolic blood pressure in an average of 14 mmHg and the same dose improved endothelial functionsignificantly, measured by blood flow in the forearm .
Scragg et al , studied the data of the NHANES 3 (Third National Health and Nutrition Examination Survey) and found a statistically significant inverse relation between VitD levels and blood pressure values, which was evident even after adjusting by variables like age, gender, ethnicity and physical activity. The average systolic blood pressure was approximately 3 mmHg lower in the individuals in the highest quintile of serum VitD in comparison to the lowest quintile .
Judd et al , also analyzed NHANES 3 data and showed a statistically significant inverse relation between concentrations of circulating VitD and systolic blood pressure. Martins et al , also on NHANES 3 data, found that a low level of VitD was associated to a greater risk of suffering hypertension.
A possible mechanism that could relate these results was analyzed in the LURIC study (Ludwigshafen Risk and Cardiovascular Health Study). This work had as its objective, to document a possible association between the different types of VitD and circulating RAS in a large cohort of patients (n=3316) with referral for coronary angiography. After measuring 25(OH) D, 1.25 (OH) 2D (both different variants of VitD), plasma renin and concentration of AngII, they could show for the first time in human beings, an independent association between them .
SHOULD WE RECOMMEND VITD SUPPLEMENTS TO PREVENT HYPERTENSION AND CARDIOVASCULAR DISEASES?
As mentioned above, many epidemiological and observational studies relate the deficiency of VitD with hypertension; however, the results of randomized studies have proven to be conflictive [39-41]. There are studies, both in vitro and in vivo, that support that this possible relation between VitD and hypertension would be due to the inhibition of RAS, highlighting the potential role of VDR as a modulator of the renin activity, particularly in hypertensive patients [19,23].
Forman et al , examined the response of the renal plasma flow to infusion of AngII in 184 normotensive individuals, stratified according to VitD levels, and later evaluated them during a diet rich in sodium. All African-American subjects that participated in the study had insufficiency or deficiency of VitD. The response obtained was overwhelming in participants with VitD deficiency. The circulating levels of AngII, but not the plasma renin activity were greater in participants with insufficiency or deficiency. The greatest activity of RAS could be the result of the low levels of plasma VitD.
The prospective studies that evaluated VitD and cardiovascular risk are less convincing. Wang et al , carried out a meta-analysis over 17 prospective cohort studies and randomized trials, and found that the supplementation with moderate to high doses of VitD may decrease the risk of cardiovascular diseases, benefitting mostly patients under dialysis treatment. Only one study on the general population showed a reduction in cardiovascular diseases after VitD supplementation . Another recent meta-analysis of 51 studies that examined the effects of VitD at cardiovascular level showed the data of these studies could not prove a statistically significant reduction in mortality or cardiovascular risk in relation to the status of VitD .
Wang et al, also examined the VitD levels inmore than 1700 participants from the Framingham study of relatives that had no prior history of cardiovascular disease . The participants with levels <37 nmol/L had an increase in their risk of incidence of cardiovascular events of 1.62 (CI 95%) compared to those participants with greater levels of VitD. However, subsequent analysis revealed that the positive findings were found in hypertensive patients, which led the investigators to propose that hypertension may intensify the adverse effects of the deficiency of VitD.
A significant prospective study, with controlled cases and on 18,000 men, showed a significant correlation between the low levels of VitD and the increase in the risk of myocardial infarction after adjusting by the traditional risk factors . More recently, the effect of the drug paricalcitol (an activated form of VitD) on the changes of the urine albumin/creatinine ratio (UACR) was compared against placebo in a randomized, double-blind study that included patients with type 2 diabetes and albuminuria (VITAL study) . After 24 weeks, a difference could not be detected between both groups. However, systolic blood pressure was significantly reduced from 3 mmHg to 9 mmHg (but fluctuating during the study) compared to the placebo group. As we see, it is still not very clear whether VitD supplements may protect against cardiovascular diseases, neither which would be the optimal serum levels to grant protection to the individuals.
The possible mechanisms underlying this relation could be explained on one side by the effects VitD has on the balance of RAS, and on the other by the antioxidation, anti-inflammatory, immunological effects, and effects on the PTH levels. These protective effects of VitD seem to extend to other fields of medicine like cancer and infections.
Which could be some coincidental point that could explain all these effects that would make it a “therapeutic panacea”? Our interpretation is that VitD could be a regulator of mitochondrial functioning [49-51], and this would be the fundamental axis of many of its effects. It has been proven that the VitD deficit affects the structure and functioning of these organelles, and that there would be receptors in the mitochondria, so the therapeutic use of VitD would protect mitochondria from damage. Answering the question, we would have to say that VitD is not an antihypertensive drug. However, it may probably play an essential role as a regulating hormone in the cardiovascular system. For this reason, knowing the plasma values of VitD of our patients and the subsequent use of supplements to normalize low levels could have an enormous importance in the evolution of hypertension and cardiovascular disease.
- Lind L, Hanni A, Lithell H, et al. Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men. Am J Hypertens 1995; 8: 894-901.
- Muller DN, Kleinewietfeld M, Kvakan H. Vitamin D review. J Renin Angiotensin Aldosterone Syst 2011;12: 125-128.
- Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266-281.
- Krause R, Buhring M, Hopfenmuller W, et al. Ultraviolet B and blood pressure. Lancet 1998; 352: 709-710.
- Peterson CA, Heffernan ME. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J Inflamm (Lond) 2008; 5: 10.
- Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension 1997; 30: 150-156.
- McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease: a narrative review. Ann Intern Med 2011; 155: 820-826.
- Isakova T, Gutierrez OM, Patel NM, et al. Vitamin D Deficiency, Inflammation, and Albuminuria in Chronic Kidney Disease: Complex Interactions. J Ren Nutr 2011; 21: 295-302.
- Bader M, Ganten D. Regulation of renin: new evidence from cultured cells and genetically modified mice. J Mol Med 2000; 78: 130-139.
- Pan L, Gross KW. Transcriptional regulation of renin: an update. Hypertension 2005; 45: 3-8.
- Persson PB, Skalweit A, Mrowka R, et al. Control of renin synthesis. Am J Physiol Regul Integr Comp Physiol 2003; 285:R491-497.
- Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 2003; 88: 327-331.
- Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002; 110: 229-238.
- Simpson RU, Hershey SH, Nibbelink KA. Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. J Steroid Biochem Mol Biol 2007; 103: 521-524.
- Yuan W, Pan W, Kong J, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007; 282: 29821-2930.
- Pilz S, Tomaschitz A, Ritz E, et al. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol 2009; 6: 621-630.
- Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol 2006; 92: 39-48.
- Kong J, Li YC. Effect of ANG II type I receptor antagonist and ACE inhibitor on vitamin D receptor-null mice. Am J Physiol Regul Integr Comp Physiol 2003; 285: R255-261.
- Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005; 288: E125-132.
- Nguyen G, Delarue F, Burckle C, et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417-1427.
- Veniant M, Menard J, Bruneval P, et al. Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 1996; 98: 1966-1970.
- Zhang Z, Sun L, Wang Y, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008; 73: 163-171.
- Zhou C, Lu F, Cao K, et al. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int 2008; 74: 170-179.
- Li YC, Qiao G, Uskokovic M, et al. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 2004; 89-90: 387-392.
- Kong J, Qiao G, Zhang Z, et al. Targeted vitamin D receptor expression in juxtaglomerular cells suppresses renin expression independent of parathyroid hormone and calcium. Kidney Int 2008; 74: 1577-1581.
- Burgess ED, Hawkins RG, Watanabe M. Interaction of 1,25-dihydroxyvitamin D and plasma renin activity in high renin essential hypertension. Am J Hypertens 1990; 3: 903-935.
- Kristal-Boneh E, Froom P, Harari G, et al. Association of calcitriol and blood pressure in normotensive men. Hypertension 1997; 30: 1289-1294.
- Resnick LM, Muller FB, Laragh JH. Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986; 105: 649-654.
- Sabanayagam C, Shankar A, Somasundaram S. Serum Vitamin D Level and Prehypertension among Subjects Free of Hypertension. Kidney Blood Press Res 2012; 35: 106-113.
- Pfeifer M, Begerow B, Minne HW, et al. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab 2001; 86: 1633-1637.
- Lind L, Wengle B, Wide L, et al. Reduction of blood pressure during long-term treatment with active vitamin D (alphacalcidol) is dependent on plasma renin activity and calcium status. A double-blind, placebo-controlled study. Am J Hypertens 1989; 2: 20-25.
- Kimura Y, Kawamura M, Owada M, et al. Effectiveness of 1,25-dihydroxyvitamin D supplementation on blood pressure reduction in a pseudohypoparathyroidism patient with high renin activity. Intern Med 1999; 38: 31-35.
- Park CW, Oh YS, Shin YS, et al. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 1999; 33: 73-81.
- Sugden JA, Davies JI, Witham MD, et al. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med 2008; 25: 320-325.
- Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens 2007; 20: 713-719.
- Judd SE, Nanes MS, Ziegler TR, et al. Optimal vitamin D status attenuates the age-associated increase in systolic blood pressure in white Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2008; 87: 136-141.
- Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2007; 167: 1159-1165.
- Tomaschitz A, Pilz S, Ritz E, et al. Independent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the renin-angiotensin system: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Clin Chim Acta 2010; 411: 1354-1360.
- Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007; 49:1063-1069.
- Burgaz A, Byberg L, Rautiainen S, et al. Confirmed hypertension and plasma 25(OH)D concentrations amongst elderly men. J Intern Med 2011; 269: 211-218.
- Major GC, Alarie F, Dore J, et al. Supplementation with calcium + vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations. Am J Clin Nutr 2007; 85: 54-59.
- Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension 2010; 55: 1283-1288.
- Wang L, Manson JE, Song Y, et al. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010; 152: 315-323.
- Bostick RM, Kushi LH, Wu Y, et al. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol 1999; 149: 151-161.
- Elamin MB, Abu Elnour NO, Elamin KB, et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96: 1931-1942.
- Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008; 117: 503-511.
- Giovannucci E, Liu Y, Hollis BW, et al. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008; 168: 1174-1180.
- de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010; 376: 1543-1551.
- Garcia IM, Altamirano L, Mazzei L, et al. Role of mitochondria in paricalcitol-mediated cytoprotection during obstructive nephropathy. Am J Physiol Renal Physiol 2012; 302: F1595-1605.
- Finch JL, Suarez EB, Husain K, et al. Effect of combining an ACE inhibitor and a VDR activator on glomerulosclerosis, proteinuria, and renal oxidative stress in uremic rats. Am J Physiol Renal Physiol 2012; 302: F141-149.
- Ferder M, Inserra F, Manucha W, et al. The world pandemic of Vitamin D deficit could possibly be explained by cellular inflammatory response activity induced by the renin angiotensin system. Am J Physiol Cell Physiol 2013, en prensa.
Publication: March 2013