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. Author manuscript; available in PMC: 2013 May 6.
Published in final edited form as: J Investig Med. 2011 Aug;59(6):868–871. doi: 10.231/JIM.0b013e31820ee448

MOLECULAR MECHANISM OF VITAMIN D IN THE CARDIOVASCULAR SYSTEM

Yan Chun Li 1
PMCID: PMC3645939  NIHMSID: NIHMS464147  PMID: 21307778

Abstract

Vitamin D deficiency is a global health problem that has various adverse consequences. Vitamin D is mainly synthesized in the skin by sunlight (UV light) irradiation; therefore, the vitamin D status is influenced by geographic locations, seasonal changes and skin pigmentations. The kidney is involved in the biosynthesis of 1,25-dihydroxyvitamin D and the reuptake of filtered 25-hydroxyvitamin D from the proximal tubules, thus vitamin D-deficiency is highly prevalent in patients with kidney disease who suffer renal insufficiency. There is a growing body of epidemiological and clinical evidence in the literature that links vitamin D deficiency to cardiovascular disease. The discovery of the vitamin D hormone functioning as an endocrine inhibitor of the renin-angiotensin system provides an explanation for this association. This review will discuss the mechanism underlying the connection between vitamin D and cardiovascular disease and its physiological and therapeutic implications.

Introduction

Vitamin D deficiency is a global health problem that has various adverse consequences 1. Vitamin D is synthesized in the skin from 7-dehydrocholesterol, and this reaction requires sunlight or ultraviolet (UV) irradiation. Vitamin D is converted in the liver to 25-hydroxyvitamin D [25(OH)D], which is the main circulating vitamin D metabolite and commonly used as an indicator of vitamin D status. 1,25-dihydroxyvitamin D [1,25(OH)2D3], the hormonal form of vitamin D, is synthesized in the kidney. Therefore, vitamin D status is influenced by geographic locations, seasonal changes and skin pigmentations 1. In addition to 1,25(OH)2D3 biosynthesis, the kidney is also required for the reuptake of filtered 25(OH)D from the proximal tubules 2, thus vitamin D-deficiency is highly prevalent in patients with kidney disease who suffer renal insufficiency 3. There is a growing body of epidemiological and clinical evidence in the literature that links vitamin D deficiency to cardiovascular disease. For example, patients with chronic kidney disease have much higher cardiovascular disease mortality at advanced stage compared to the general population 4. The discovery of the vitamin D hormone functioning as an endocrine inhibitor of the renin-angiotensin system (RAS) provides an explanation for this association. Here I will discuss the potential mechanism underlying the connection between vitamin D and cardiovascular disease and its physiological and therapeutic implications, with a focus on the RAS.

Association of Vitamin D Deficiency with Cardiovascular Disease

UV irradiation is required for the cutaneous synthesis of vitamin D. UV irradiation decreases with the increase in latitude, and high latitudes are correlated with high prevalence of hypertension and stroke incidents 5, 6. Winter season, which has low UV irradiation, is associated with high incidence of myocardial infarction 7. Dark skin pigmentation in the black population, which blocks UV light penetration, is associated with higher blood pressure 8, 9. Data from the National Health and Nutrition Examination Surveys (NHANES) III showed an inverse relationship between serum 25(OH)D and blood pressure in the general population 10. The NHANES III database also revealed an inverse correlation between serum 25(OH)D levels and the prevalence of cardiovascular risk factors including hypertension, diabetes, obesity and hyperlipidemia 11. Low vitamin D status was thought to be a contributing factor for congestive heart failure 12. A recent meta-analysis of 18 published studies confirms the inverse relationship between blood 25(OH)D levels and hypertension 13.

Other epidemiological studies have confirmed the association between vitamin D-deficiency and increased risk of cardiovascular problems. Prospective studies with cohorts from the Health Professionals’ Follow-Up Study (HPFS) and the Nurses’ Health Study (NHS) showed that serum 25(OH)D levels are inversely associated with the risk of incident hypertension during 4 years of follow-up 14. A nested case-control prospective study using the HPFS database also demonstrated an association of low serum 25(OH)D levels with higher risk of myocardial infarction, even after adjusting for factors known to be associated with coronary artery disease 15. Low serum 25(OH)D is also associated with incident cardiovascular disease in Framingham Offspring Study participants without prior cardiovascular disease during a mean follow-up of 5.4 years, after adjustment for C-reactive protein, physical activity or vitamin use 16. Therefore, vitamin D-deficiency is a risk factor for cardiovascular disease.

The Renin-Angiotensin System as a Major Target of Vitamin D

The renin-angiotensin system (RAS) is a regulatory cascade that has profound impact on the cardiovascular system. Renin is the rate-limiting step of the RAS cascade that converts angiotensinogen (AGT) to angiotensin (Ang) I. Angiotensin-converting enzyme (ACE) then converts Ang I to Ang II, the biological effector of the RAS. Systemic Ang II is a central regulator of blood pressure through increasing vasoconstriction, extracellular volume and cardiac output, and over-activation of the RAS results can lead to hypertension 17, 18. In addition to blood pressure control, Ang II has diverse pathological activities that promote fibrogenesis, inflammation, cell hypertrophy and proliferation 19-21. Thus over-activation of the RAS is detrimental.

Recent studies have well established the RAS as a major target of vitamin D, which may in part serve the link between vitamin D-deficiency and cardiovascular disease. In fact, two early articles reported an inverse relationship between circulating 1,25(OH)2D3 levels and plasma renin activity in hypertensive subjects more than two decades ago 22, 23; however, the significance of these studies was hardly recognized until the discovery that 1,25(OH)2D3 is a negative endocrine regulator of renin production 24. This discovery stemmed from our initial observation that vitamin D receptor (VDR)-null mice, a complete vitamin D-deficient model 25, develop hyperreninemia due to dramatic up-regulation of renin expression in the kidney 24. Plasma renin activity, plasma Ang II and plasma and urinary aldosterone levels in VDR-null mice are markedly elevated, leading to development of high blood pressure, cardiac hypertrophy and polyuria 24, 26, 27. Interestingly, polyuria seen in VDR-null mice appears to result from overdrinking due to up-regulation of renin in the central nerve system and activation of the brain RAS 28.

The critical role of vitamin D in RAS regulation was confirmed in another genetic model of vitamin D-deficiency, the Cyp27b1-null mice. These mice lack 1α-hydroxylase that is required for the biosynthesis of 1,25(OH)2D3. Similar to VDR knockout mice, Cyp27b1 knockout mice also develop hyperreninemia, hypertension and cardiac hypertrophy as a result of renin up-regulation, but these abnormalities could be corrected by exogenous 1,25(OH)2D3 administration 29. Moreover, we have taken a transgenic approach to confirm the inhibitory role of 1,25(OH)2D3 in renin expression. We showed that in transgenic mice that overexpress the human VDR in the juxtaglomerular cells, renal renin mRNA levels and plasma renin activity are significantly suppressed while serum calcium and parathyroid hormone levels are normal. Furthermore, the VDR transgene is able to rescue the hyperreninemia phenotype when introduced into VDR-null mice through breeding 30. We have also reported that pharmacological dose of vitamin D analogs can effectively inhibit renin expression in mice 31. Together these data establish the vitamin D hormone as a crucial negative endocrine regulator of the RAS.

The relevance of vitamin D regulating the RAS in humans has been confirmed in a number of recent studies. Epidemiological data from a large cohort of patients (>3000) referred for coronary angiography in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study demonstrated that both serum 25(OH)D and 1,25(OH)2D3 levels are independently and inversely associated with plasma renin concentration and Ang II levels 32. Vitamin D analog therapy has been reported to significantly suppress plasma renin activity in patients with late stage chronic kidney disease 33.

We have shown that 1,25(OH)2D3 inhibits renin gene transcription by targeting the cyclic AMP signaling pathway 34, a signaling pathway that plays a critical role in renin biosynthesis and release in response to various physiological factors 35. CREB and/or CREM interact with the cyclic AMP response element (CRE) in the renin gene promoter. Phosphorylation of CREB or CREM by PKA leads to recruitment of CBP/p300 to the CRE site to drive renin gene transcription. In the presence of 1,25(OH)2D3, ligand-activated VDR physically interacts with CREB, blocking CREB binding to the CRE and thus disrupting the formation of CREB-CBP/p300 complex on the CRE site. As a consequence, renin transcription is stopped. This is at least part of the molecular mechanism by which 1,25(OH)2D3 inhibits renin production. This mechanism is a basis to use vitamin D and its analogs as inhibitors to inhibit renin production.

Therapeutic Potentials of Vitamin D Analogs in Cardiovascular Disease

Because of its profound effect on the cardiovascular system, the RAS has been a major therapeutic target for prevention and intervention of cardiovascular disease. Small molecules that target the RAS, including ACE inhibitors (ACEI), Ang II type 1 receptor blockers (ARB) and renin inhibitors, are widely used anti-hypertensive drugs 36-38. The notion that 1,25(OH)2D3 suppresses renin biosynthesis provides a molecular basis to explore vitamin D and vitamin D analogs as novel RAS inhibitors for therapeutic purposes. Bodyak et al reported that treatment with paricalcitol (19-nor-1,25-dihydroxyvitamin D2), an activated vitamin D analog, blocked high salt-induced cardiac hypertrophy in the Dahl salt-sensitive rat model 39. Surrogate biomarkers of hypertrophy such as ANP and BNP were significantly suppressed by the treatment, together with a marked reduction of cardiac renin expression. In the rat model of chronic renal failure (5/6 nephrectomy) paricalcitol treatment significantly lowered blood pressure and suppressed the RAS in the remnant kidney 40. In an early study, 15-weeks intravenous infusion of calcitriol (1,25(OH)2D3) was shown to regress left ventricular hypertrophy in hemodialysis patients 41. Interestingly, in this study the reduction in the left ventricular mass was accompanied by a significant reduction in plasma renin activity, plasma Ang II and ANP levels in these patients, consistent with the suppressive effect of 1,25(OH)2D3 on the RAS.

A major problem associated with the current RAS inhibitors is the compensatory increase of renin concentration 42. As the rate-limiting step of the RAS, renin homeostasis is maintained by the negative feedback loop mediated by the AT1 receptor. Blockade of the RAS simultaneously disrupts the negative feedback loop, leading to up-regulation of renin expression. The huge increase in renin concentration and activity in the plasma and tissue interstitial space stimulates the conversion of Ang I, which can ultimately lead to the build-up of Ang I, Ang II and other angiotensin metabolites in the body, through ACE-dependent and -independent pathways (Figure 1). Ang II accumulation compromises the efficacy of RAS inhibition and may explain why the current RAS inhibitors are only clinically suboptimal.

Figure 1.

Figure 1

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Vitamin D analogs block the compensatory induction of renin in combination therapy. The homeostasis of renin production is maintained by the negative feedback loop mediated by AT1 receptor. Inhibition of the RAS by the three classes of inhibitors (renin inhibitors, ACE inhibitors and ARB) disrupts the feedback loop leading to increased renin production. Ultimately Ang II levels can be raised, which reduces reduced the efficacy of the drugs. In combination therapy, vitamin D analogs are able to block the compensatory increase of renin by suppressing renin gene expression, and that improves the therapeutic efficacy.

One important application of vitamin D analogs is to block the compensatory renin increase at the transcriptional level in combination therapy with the classic RAS inhibitors 43 (Figure 1). The combination is expected to enhance the efficacy of RAS inhibition and achieve better therapeutic outcomes 44. Recently we demonstrated that a combination of paricalcitol or doxercalciferol (1α-hydroxyvitamin D2) with losartan blocks cardiac hypertrophy in spontaneously hypertensive rats much more effectively than each mono-treatment 33. Spontaneously hypertensive rats, a model of human essential hypertension, develop age-dependent left ventricular hypertrophy. The rats were treated for 2 months with losartan, paricalcitol, doxercalciferol, losartan and paricalcitol combination or losartan and doxercalciferol combination. Left ventricular mass was quantified by echocardiography, and hypertrophic markers such as ANP and BNP were also measured. While paricalcitol or doxercalciferol reduced left ventricular hypertrophy as effectively as losartan in mono-treatment, the combinations had much better therapeutic efficacy than the three mono-therapies. Indeed, the compensatory increase of renin in the kidney and heart was blocked in the combination therapy 33. Similar findings were observed with the combination therapy in models of diabetic nephropathy 45-47. In humans, a recently reported large randomized clinical trial (the VITAL Study) confirmed that paricalcitol was able to reduce albuminuria and blood pressure in patients with diabetic nephropathy who were already on RAS inhibitor therapy 48. Direct renin inhibitors such as aliskiren also have the problem of inducing a huge increase in plasma renin concentration 49, and it is expected that combination of aliskiren with a vitamin D analog should also lead to blockade of the compensatory renin induction and improvement of the therapeutic efficacy of aliskiren 44 (Figure 1). Therefore, the combination of vitamin D analogs and RAS inhibitors has broad therapeutic potentials. Given the wide use of RAS inhibitors in cardiovascular disease, the combination strategy warrants further investigations in clinical settings. In fact, the ongoing PRIMO study (ClinicalTrials.gov Identifier: NCT00497146; Enrollment: 220 stage 3 and 4 CKD patients), a randomized double-blind placebo control clinical trial that investigates the effect of paricalcitol on the progression of left ventricular hypertrophy in stage 3 and 4 CKD patients who are already on RAS inhibitors, will assess the cardiac outcome of the combination of vitamin D analog and RAS inhibitors in humans.

Conclusion

The finding of the vitamin D hormone as a negative endocrine regulator of the RAS has important physiological and clinical significance. It suggests that the vitamin D endocrine system may maintain the homeostasis of the cardiovascular system through suppressing the RAS, and vitamin D-deficiency or insufficiency may lead to activation of the RAS, thus increasing the risk of cardiovascular disease. Vitamin D analogs as novel renin inhibitors have great therapeutic potentials for cardiovascular disease. Combination therapy with vitamin D analogs and RAS inhibitors can enhance the therapeutic efficacy in the treatment of cardiovascular disease.

Abbreviations

VDR

vitamin D receptor

RAS

renin-angiotensin system

AGT

angiotensinogen

Ang

angiotensin

ACE

angiotensin-converting enzyme

1,25(OH)2D3

1,25-dihydroxyvitamin D3

Footnotes

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