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 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 from 25(OH)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 have 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 National Health and Nutrition Examination Surveys 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 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 Health Professionals' Follow-Up Study 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 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 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 overactivation of the RAS 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, overactivation 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, 2 early articles reported an inverse relationship between circulating 1,25(OH)2D3 levels and plasma renin activity in hypertensive subjects more than 2 decades ago22,23; 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 because of 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 seems 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, which 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 messenger RNA levels and plasma renin activity are significantly suppressed, whereas 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 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 Cyclic AMP response element binding protein (CREB) and/or cyclic AMP response element modulator interact with the cyclic AMP response element (CRE) in the renin gene promoter. Phosphorylation of CREB or cyclic AMP response element modulator by protein kinase A 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 antihypertensive 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 al39 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. Surrogate biomarkers of hypertrophy such as atrial natriuretic peptide and brain natriuretic peptide 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 of 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 and plasma Ang II and atrial natriuretic peptide 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 Ang II type 1 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 ACE-independent pathways (Fig. 1). Ang II accumulation compromises the efficacy of RAS inhibition and may explain why the current RAS inhibitors are only clinically suboptimal.
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 (Fig. 1).43 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 monotreatment.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 atrial natriuretic peptide and brain natriuretic peptide were also measured. Although paricalcitol or doxercalciferol reduced left ventricular hypertrophy as effectively as losartan in monotreatment, the combinations had much better therapeutic efficacy than the 3 monotherapies. 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 SelectiVe ParicalcITol for Albuminuria Lowering 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 the 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 (Fig. 1).44 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 Paricalcitol Capsules Benefits in Renal Failure Induced Cardiac Morbidity in Chronic Kidney Disease Stage 3/4 study (ClinicalTrials.gov Identifier: NCT00497146; enrollment: 220 stage 3 and stage 4 chronic kidney disease patients), a randomized double-blinded placebo control clinical trial that investigates the effect of paricalcitol on the progression of left ventricular hypertrophy in stage 3 and stage 4 chronic kidney disease patients who are already on RAS inhibitors, will assess the cardiac outcome of the combination of vitamin D analog and RAS inhibitors in humans.
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.
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