Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines. We also found that the vitamin D receptor was transiently expressed during MAC differentiation and that in vitro, calcitriol increased differentiation of monocytes into MACs in both SLE and in a model using the prototypic SLE cytokine, interferon-alpha. The active form of vitamin D (calcitriol) restored the SLE MAC phenotype towards that of healthy subjects with reduced IL-6 secretion, and normalised surface marker expression. Calcitriol also augmented the angiogenic capacity of MACs via the down-regulation of CXCL-10. In SLE patients treated with cholecalciferol for 12 weeks, the improvement in endothelial function correlated with increase in serum 25(OH)D concentrations independently of disease activity. We also show that MACs were able to positively modulate eNOS expression in human endothelial cells in vitro, an effect further enhanced by calcitriol treatment of SLE MACs. The results demonstrate that vitamin D can positively modify endothelial repair mechanisms and thus endothelial function in a population with significant cardiovascular risk

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Low vitamin D status is associated with systemic and gastrointestinal inflammation in dogs with a chronic enteropathy

Vitamin D is traditionally known for its role in calcium homeostasis and bone metabolism. However, it has been demonstrated that numerous types of cells express the vitamin D receptor and it is now clear that the physiological roles of vitamin D extend beyond the maintenance of skeletal health. Vitamin D insufficiency, which is typically assessed by measuring the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with a number of disorders in people including hypertension, diabetes, cardiovascular diseases, cancer, autoimmune conditions and infectious diseases. Meta-analyses have demonstrated that serum 25(OH)D concentrations are an important predictor of survival in people with a wide variety of illnesses and have been linked to all-cause mortality in the general human population. The role of vitamin D in non-skeletal disorders in cats and dogs is poorly understood. This is surprising since cats and dogs could act as excellent models for probing the biology of vitamin D. Vitamin D status in people is largely dependent on cutaneous production of vitamin D. This is influenced by many factors such as season, latitude and exposure to ultraviolet (UV) radiation. The interpretation of human studies investigating the effects vitamin D status on disease outcomes are therefore influenced by a number of confounding variables. Unlike humans, domesticated cats and dogs do not produce vitamin D cutaneously and obtain vitamin D only from their diet. The physiological functions and regulation of vitamin D are otherwise similar to humans. Most pets are fed commercial diets containing a relatively standard amount of vitamin D. Consequently, companion animals are attractive model systems in which to examine the relationship vitamin D status and health outcomes. Furthermore, spontaneously occurring model systems which did not require disease to be induced in healthy animals would allow the numbers of animals used in scientist research to be reduced. This thesis aimed to define vitamin D homeostasis in companion animals in three disease settings; in cats with feline immunodeficiency virus (FIV) infection, dogs with chronic enteropathies (CE) and in hospitalised ill cats. Additional aims were to assess the prognostic significance of serum 25(OH)D concentrations in companion animals and the relationship between serum 25(OH)D concentrations and markers of inflammation. The hypothesis of this thesis was that vitamin status D would negatively correlate with presence of disease, markers of inflammation and disease outcomes. As similar findings have been demonstrated in human medicine, the hypothesis was that cats and dogs would be suitable models to investigate the role of vitamin D in human disease. This thesis demonstrates that in dogs with a CE serum 25(OH)D concentrations are negatively correlated with inflammation and are predictive of clinical outcomes. Vitamin D status was also lower in cats with FIV and importantly vitamin D status was predictive of short term mortality in hospitalised ill cats. This research will be of interest to veterinary surgeons and opens the possibility for clinical trials which examine if low vitamin D status is causally associated with ill health and whether vitamin D supplementation results in superior treatment outcomes in companion animals. This thesis also demonstrates the potential of cats and dogs as model systems in which to examine the role of vitamin D in human health