Current Drug Targets - Volume 12, Issue 1, 2011

The fat-soluble secosteroid hormone vitamin D is best known for its role in bone metabolism. From a historical perspective, the study of vitamin D deficiency has been intimately related to the study of (possible treatment of) rickets. Although diseases characterized by bone deformations have been described in ancient medical writings from the 1st and 2nd centuries, it was Galen who described the classic bone deformities noted in rickets [1, 2]. More clear descriptions originate from the 17th century, reporting rickets to be endemic in England [1]. In the early 20th century, observations that artificial UV light or sunlight provides protection against rickets coincided with results suggesting that rickets may be the consequence of a nutritional deficiency [3, 4]. The responsible vitamin was identified by McCollum et al., who stated in their paper in the Journal of Biological Chemistry in 1922: “These experiments clearly demonstrate the existence of a fourth vitamin whose specific property, as far as we can tell at present, is to regulate the metabolism of the bones” [5]. This “fourth vitamin” was named vitamin D. Once vitamin D deficiency had been identified as the cause of rickets, halfway the 20th century many governments decided to have foods (e.g. dairy and orange juice) fortified with vitamin D in order to conquer this deforming disease. Since then, rickets has become rare in the Western world. However, rickets can be considered “the tip of the vitamin D-deficiency iceberg” [6], as less severe vitamin D deficiency may compromise optimal function of several organ systems, such as the cardiovascular and renal system. A growing number of recent studies indicate that the sum of vitamin D generated in the skin and obtained from the diet is insufficient to maintain adequate circulating vitamin D levels in a considerable part of the population worldwide, as reviewed by Dr. Holick in this issue [7]. Thus, although rickets has become rare, the extent of the vitamin D deficiency pandemic, estimated to affect about a billion people worldwide, and its health consequences are matters that urgently require attention. This Special Issue addresses the potential role of vitamin D deficiency in the pathogenesis and progression of cardiovascular and renal disease. A number of renowned authors will tackle the question whether vitamin D deficiency may be a risk factor for cardiovascular disease, and whether treatment with vitamin D (analogues) could be a beneficial intervention in cardiovascular and/or renal disease. A first important hurdle in epidemiological research to investigate the association between vitamin D levels and certain diseases is a methodological one. Most experts agree that vitamin D deficiency can be defined as a low circulating level of the pro-hormone 25-OH vitamin D. However, it is uncertain which is the optimal method to properly measure 25-OH vitamin D levels, not in the last place since vitamin D levels are in the nanomolar range and many structurally highly similar metabolites exist. In this issue, Dr Carter, involved in the DEQAS (vitamin D external quality control programme) initiative, provides an excellent overview comparing various laboratory measurements and exploring the possibilities and pitfalls of these techniques [8]. In spite of methodological issues, a number of epidemiological studies have related vitamin D deficiency to increased risk of cardiovascular disease, but robust data from large randomized controlled trials are lacking. In this issue, Dr. Meems et al. systematically review the available data addressing potential cardioprotective effect of vitamin D analogues in heart failure [9], while the possible relationship between vitamin D deficiency and vascular disease is covered by Brewer et al. [10]. Although vitamin D may directly protect the heart and/or blood vessels, there could also be more indirect protective pathways. For example diabetes mellitus, a major risk factor for cardiovascular disease, may be modulated by vitamin D analogues. Indeed several studies suggest that vitamin D supplementation could be beneficial in diabetic subjects, although major question are still unanswered. Dr. Boucher addresses the potential relationship between vitamin D deficiency and diabetes [11]. In many patients, atherosclerosis results in end-organ damage on the long term. Besides the heart and vasculature, atherosclerosis may affect the kidneys and brain. Recent studies in diabetic animal models have revealed that vitamin D protects against diabetic nephropathy on top of standard treatment, in an impressive manner [12]. But also in non-diabetic renal disease, treatment with vitamin D analogues is beneficial [13]. Dr. Mirkovic provides an overview of recent studies on renoprotective effects of vitamin D in this Special Issue [14]. Dr. Pilz et al. will summarize all available data on the cerebroprotective potential of vitamin D (analogues) [15]. In summary, the potential protective role of vitamin D and/or its synthetic analogues is currently under investigation for a wide range of complex diseases. The preliminary positive findings documented until now suggest that vitamin D has pleiotropic effects, and raise the question whether vitamin D deficiency may be a universal risk factor for multifactorial disease. In the last paper of this issue, we will attempt to identify a limited number of molecular pathways shared by several types of complex disease, that could be regulated by vitamin D [16]. Ultimately, clinical trials should provide the evidence that vitamin D supplementation could indeed provide cardiovascular and/or renal protection. As such trials are currently ongoing, the coming years will hopefully bring answer to the question whether vitamin D could be a new cornerstone therapy for the treatment of cardiovascular and renal disease.

Vitamin D, the sunshine vitamin, has been important not only for the evolution of a healthy calcified vertebrate skeleton but it also evolved into a hormone that has a wide diversity of biologic effects. During exposure to sunlight the ultraviolet B radiation converts 7-dehydrocholesterol to previtamin D3 which in turn rapidly isomerizes to vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and in the kidneys to its active form 1,25- dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 interacts with its vitamin D receptor in calcium regulating tissues to regulate calcium metabolism and bone health. It is now recognized that most cells in the body have a vitamin D receptor and they also have the capability of producing 1,25-dihydroxyvitamin D3 which in turn is capable of regulating a wide variety of genes that have important functions in regulating cell growth, modulating immune function and cardiovascular health. Epidemiologic evidence and prospective studies have linked vitamin D deficiency with increased risk of many chronic diseases including autoimmune diseases, cardiovascular disease, deadly cancers, type II diabetes and infectious diseases. Vitamin D deficiency and insufficiency have been defined as a 25-hydroxyvitamin D <20 ng/ml and 21-29 ng/ml respectively. For every 100 IU of vitamin D ingested the blood level of 25-hydroxyvitamin D, the measure vitamin D status, increases by ∼1 ng/ml. It is estimated that children need at least 400-1000 IU of vitamin D a day while teenagers and adults need at least 2000 IU of vitamin D a day to satisfy their body's vitamin D requirement. It is estimated that 1 billion people worldwide are vitamin D deficient or insufficient. Correcting and preventing this deficiency could have an enormous impact on reducing health costs worldwide.

Measurement of 25-hydroxyvitamin D (25-OHD) is widely used for assessing vitamin D status. There has been a dramatic increase in 25-OHD requests over recent years prompting many laboratories to consider the use of automated immunoassays. To achieve higher throughput, these methods have abandoned the traditional solvent extraction of samples and are therefore more prone to non-specific interference. The Vitamin D External Quality Assessment Scheme (DEQAS) has revealed method-related differences in 25-OHD results, raising concerns about the comparability and accuracy of different assays. This paper highlights some of the pre-analytical, analytical and post-analytical issues which may influence the accuracy of 25-OHD assays and interpretation of results. Recent attention has focused on reconciling the relatively high results given by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to those of the DiaSorin radioimmunoassay (RIA) on which clinical decision points have previously been based. Data is presented on 20 DEQAS samples which were analysed by an LC-MS/MS assay developed as a candidate reference measurement procedure by the US National Institute of Standards and Technology (NIST). The NIST results were on average 11.2% lower than those given by routine LC-MS/MS methods. If confirmed, these results suggest that most routine LC-MS/MS assays are perhaps overestimating 25-OHD by failing to resolve a molecule having the same mass as 25-OHD3 and a similar fragmentation pattern. All 25-OHD assays should be monitored by a proficiency testing scheme and the results made available to clinicians and editors of scientific journals.

Vitamin D has recently been suggested as an important mediator of blood pressure and cardiovascular disease, including heart failure. In patients with heart failure, low vitamin D levels are associated with adverse outcome and correlate with established clinical correlates and biomarkers. Many precursor states of heart failure, such as hypertension, atherosclerosis, and diabetes are more prevalent in subjects with low vitamin D levels. Recent experimental data have provided clues how vitamin D might exert cardioprotective effects. The steroid hormone vitamin D regulates gene expression of many genes that play a prominent role in the progression of heart failure, such as cytokines and hormones. Specifically, vitamin D is a negative regulator of the hormone renin, the pivotal hormone of the renin-angiotensin system. Mechanistic insights were gained by studying mice deficient for the vitamin D receptor, which develop hypertension and adverse cardiac remodeling mediated via the renin-angiotensin system. Furthermore, vitamin D receptor is expressed in the heart and regulated under pro-hypertrophic stimuli and vitamin D as receptor has been associated with the expression of other hypertrophic genes such as natriuretic peptides. So, epidemiological data and mechanistic studies have provided strong support for a potentially cardioprotective effect of vitamin D. It remains unclear if vitamin D supplementation is beneficial in preventing heart failure or if it could be a therapeutic addendum in the treatment of heart failure. This review summarizes current knowledge on vitamin D and its biology in heart failure.

Prevention of progressive renal function loss and its complications remains the main challenge in clinical nephrology. Although current therapeutic strategies aiming at reduction of blood pressure and proteinuria often slow down deterioration of renal function, still many patients progress to end-stage renal disease. The development of novel pharmacological approaches for treatment of chronic kidney disease (CKD) is therefore instrumental. Here we review the renoprotective potential of vitamin D and its analogues. In CKD patients, vitamin D deficiency is common and progression of CKD is associated with low (active) vitamin D levels. Moreover, in animal models of CKD, treatment with vitamin D (analogues) alone or in combination with renin-angiotensin-aldosterone system (RAAS) blockade reduces proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Potential underlying mechanisms include suppression of the RAAS, modulation of immune cell function and direct protective effects on renal cells such as podocytes. Whether vitamin D analogues could further optimize existing therapies in human renal disease is currently under investigation.

Vitamin D deficiency has been linked to an increased risk of hypertension, diabetes, congestive heart failure, peripheral arterial disease, myocardial infarction, stroke, and related mortality, even after adjustment for traditional cardiovascular risk factors. Accumulating evidence from experimental, clinical, and epidemiological studies suggests that vitamin D may also be associated with several indices of vascular function, including the development and progression of atherosclerotic cardiovascular disease. These findings may provide at least a partial explanation for several recent epidemiologic studies implicating low vitamin D status in the pathogenesis of cardiovascular disease. However, many questions still remain. Only a handful of studies are currently available, and the results of these studies have generally been mixed. Additionally, it is unknown whether findings differ across varied subpopulations, including minority subgroups in the United States, younger adults, and those residing in areas with varying amounts of regular sunlight. Furthermore, the exact mechanism by which vitamin D may influence the atherosclerotic disease process has not yet been completely elucidated. In addition, if vitamin D is important in the etiology of atherosclerosis, it is unclear at what stage(s) in the atherosclerotic disease process vitamin D may exert its effects. Large-scale, well-conducted, placebo controlled clinical trials testing the efficacy of vitamin D supplementation in delaying, slowing, or reverting the atherosclerotic disease process have not yet been conducted. Until the results of these studies are available, we believe it is premature to recommend vitamin D as a therapeutic option in atherosclerosis.

Diabetes is an increasing epidemic; hyperglycemia results from lack of insulin or inadequate insulin secretion following increases in insulin resistance. Huge costs are placed upon sufferers and health providers, aggravated as serious and disabling complications develop. Thus, measures to reduce the diabetic burden are public health concerns. Vitamin D, identified ∼100 years ago, promotes calcium absorption and utilization, preventing and curing rickets and osteomalacia. Calcium is necessary for insulin secretion, suggesting vitamin D may contribute to maintaining insulin secretion. Vitamin D, formed in skin in bright sunshine, is scarce in foodstuffs. Data linking hypovitaminosis D to hyperglycemia, type 2 diabetes (T2DM) and metabolic disorders increasing cardiovascular risk [metabolic ‘syndrome’] has accumulated over ∼40 years. Many mechanisms are known whereby hypovitaminosis D could be causal, e.g. by increasing insulin resistance, reducing insulin secretion and increasing autoimmune or inflammatory damage to pancreatic islets. Major questions still to be answered are whether increasing vitamin D status to the maximum seen in healthy people would reduce the risk of diabetes, the severity of the disease or of its complications, including cardiovascular disease. These questions urgently require answers. If on-going/ planned RCTs confirm causality, maintenance of adequate vitamin D status at the population level by food-fortification or supplementation would be cost-effective measures likely to reduce the burden and costs of diabetes to individuals and health services. Additionally, vitamin D2/3 supplementation is cheap but whether some non-hypercalcemia-inducing analogue may prove safer has not yet been addressed at the population level.

Vitamin D deficiency is highly prevalent due to lifestyle and environmental factors which limit sunlight induced vitamin D production in the skin. This “pandemic” of vitamin D deficiency is of concern because low levels of 25-hydroxyvitamin D (25[OH]D) have been associated with cardiovascular, musculoskeletal, infectious, autoimmune and malignant diseases. Epidemiological studies have largely but not consistently shown that vitamin D deficiency is a risk factor for strokes. This is supported by associations of low 25(OH)D levels with cerebrovascular risk factors, in particular with arterial hypertension. Vitamin D has also been shown to exert neuroprotective, neuromuscular and osteoprotective effects which may reduce cognitive and functional impairments in poststroke patients. Hence, the current literature favours the notion that vitamin D supplementation is a promising approach for the prevention and treatment of strokes but accurate data from interventional studies are missing. Randomized controlled trials are therefore urgently needed to evaluate whether vitamin D supplementation reduces the incidence of strokes and improves the outcome of poststroke patients. We do, however, believe that currently published data on the multiple health benefits of vitamin D and the easy safe and inexpensive way by which it can be supplemented already argue for the prevention and treatment of vitamin D deficiency in order to reduce stroke associated morbidity and mortality.

In the Western world, the majority of morbidity and mortality are caused by multifactorial diseases. Some risk factors are related to more than one type of disease. These so-called universal risk factors are highly relevant to the population, as reduction of universal risk factors may reduce the prevalence of several types of multifactorial disease simultaneously. Vitamin D deficiency is traditionally seen as an etiological factor in bone disorders such as rickets and osteomalacia. Recent studies also suggest a role for vitamin D deficiency in multifactorial disorders, including progressive renal function loss and cardiovascular disease; it is also a risk factor for frailty. The potentially pleiotropic effects of vitamin D analogues support the hypothesis that vitamin D deficiency is a universal risk factor. Here we review molecular actions of the vitamin D receptor (VDR), to identify mechanisms and pathways for vitamin D deficiency as a universal risk factor. To identify genes directly regulated by the VDR, we searched for genes containing vitamin D response elements (VDREs). A further refinement was made by selecting only VDRE-containing genes with documented modulation by VDR analogues in vivo. Our search yielded a limited number of factors possibly related to pleiotropic effects of vitamin D, including growth factors, hormones, inflammatory factors and factors related to calcium homeostasis. Results from observational, intervention and mechanistic studies indicate that vitamin D is a universal risk factor involved in diverse multifactorial conditions. Further exploration of the multifaceted actions of vitamin D may pave the way for disease-overriding intervention strategies.

Diabetic nephropathy (DN) is a common complication of diabetes mellitus and is the primary cause of endstage renal disease in the Western World. Vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of DN of type 1 diabetes mellitus. VEGF is the main angiogenic factor and a potent mitogen for endothelial cells. It is mainly produced in kidney by podocytes and exerts its biological activities by binding to its receptors (VEGFRs). Alternative splicing of a single VEGF gene produces various isoforms and two families with anti- and pro-angiogenic properties. In normal glomeruli, VEGF isoforms are in tight regulation and act in a paracrine and an autocrine manner preserving the integrity of glomerular filtration barrier. Many mediators in diabetic milieu induce the expression of VEGF and possibly the VEGFxxx isoform in animal models of type 1 diabetes, however, in human kidney with developed DN, VEGF expression seems to be lower or absent. Inhibition of VEGF in experimental DN ameliorates structural and functional changes and proposes possible therapeutic targets. Further studies are required before these treatments can be used in diabetic patients at early stages of DN.

Aortic stenosis is the most common valvular heart disease among adult subjects in western countries. The current treatment for aortic stenosis is aortic valve replacement. The possibility of a medical treatment that can slow the progression of aortic stenosis is very fascinating and statins have been tested to reduce the progression of degenerative aortic stenosis (DAS). The rationale for statin treatment in DAS has a deep pathophysiological substrate; in fact inflammation and lipid infiltration constitute the same histopathological pattern of both aortic stenosis and atherosclerosis and these two conditions have the same risk factors. Whether retrospective studies have shown some efficacy of statins in halting the progression of DAS, prospective trials have shown controversial results. A recently published large and randomized controlled trial SEAS found that statins have no significant effect on the progression of aortic stenosis, the ASTRONOMER, recently confirmed this data. The most plausible hypothesis is that coronary artery disease and DAS, have a common pathogenetic background and a distinct evolution due to different factors (mechanical stress, genetic factors, interaction between inflammatory cells and calcification mediators). Thus, treatment with statins is not recommended in patients with valvular aortic stenosis and without conventional indications to lipid-lowering treatment.

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. “-Omics” technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures.