Work by Wiseman (1993) has shown that vitamin D3 (cholecalciferol), its active metabolite 1,25-dihydroxycholecalciferol, Vitamin D2 (ergocalciferol), and 7-dehydrocholesterol (pro-Vitamin D3) are all membrane antioxidants by virtue of their abilities to inhibit iron-dependent liposomal lipid peroxidation. There are very few studies focusing on the potential role of vitamin D as an antioxidant in biological systems. One such study by Sardar et al. (1996) found that vitamin D3 may function as an in vivo antioxidant in the rat liver with an effectiveness higher than that observed with vitamin E supplementation. It is unlikely that vitamin D in plasma could be an effective antioxidant since its levels are very low, i.e. the levels of 25 (OH)D3 and other vitamin D metabolites in healthy persons are between 6O and 1OOnM. In contrast, plasma vitamin E levels are between 15—3O y«M, which is at least 25O times higher than the typical plasma levels of vitamin D. At present, there are no data suggesting that vitamin D functions to prevent cardiovascular disease by virtue of its potential role as an antioxidant.
68 Functional foods, cardiovascular disease and diabetes 4.3.2 Vitamin D and heart disease
Vitamin D deficiency is a risk factor for the development of cardiovascular disease and diabetes but the molecular mechanisms are not yet fully understood (Timms et al., 2002). A variety of possible mechanism will be discussed and critically evaluated below.
Grimes et al. (1996) investigated the potential relationship between geography and incidence of coronary heart disease. They suggested that sunlight deficiency could increase blood cholesterol by allowing squalene metabolism to progress to cholesterol synthesis rather than to vitamin D synthesis. They did indeed find higher levels of blood cholesterol during the winter months and suggested this could be due to reduced sunlight exposure. This suggestion is, however, somewhat speculative since it is not clear that vitamin D and its metabolites are a quantitatively significant fraction of squalene metabolism.
Vitamin D, insulin secretion, and diabetes
Vitamin D deficiency appears to have a very plausible relationship to type II diabetes in which defects in insulin secretion or in insulin signaling may be important factors. In animal models it has been found that 1,25-dihydroxyvitamin D3 deficiency inhibits the pancreatic secretion of insulin (Norman et al., 1980) and that this effect is only partially dependent upon serum calcium levels (Kadowaki and Norman, 1984, 1985). Subsequent work also showed that vitamin D3 improved impaired glucose-tolerance in vivo as well as insulin secretion in rats deficient in vitamin D3 (Cade and Norman, 1986).
Boucher et al. (1995) assessed the vitamin D status of Bangladeshi Asians living in East London and found that serum 25-OH vitamin D was reduced in those at risk for developing type II diabetes compared with subjects not at risk. The subjects in this study were also subjected to an oral glucose tolerance test (OGTT), in which a load of 75 g glucose in 300 ml water was consumed after an overnight fast and venous blood samples drawn at 0, 15, 30, 60, and 120min for blood glucose, serum insulin and serum C-peptide assays. Early phase insulin secretion was assessed by measuring serum insulin 30min after the oral glucose load. Boucher et al. (1995) found a positive correlation between early phase insulin secretion and serum levels of 25-OH vitamin D. Glucose intolerance was also correlated with vitamin D deficiency. Short-term vitamin D replenishment increased insulin secretion in a subset of subjects but did not alter the subjects' glucose intolerance.
The mechanism whereby vitamin D influences insulin secretion is not clear but it is reasonable to suggest that vitamin D receptors could be important in this regard. It is very interesting, therefore, that the insulin-producing beta cells of the pancreas have receptors that are specific for 1,25-dihydroxyl vitamin D3 (Ishida et al., 1988). Moreover, Hitman et al. (1998) found that vitamin D receptor gene polymorphisms can influence insulin secretion in Bangladeshi Asians. Subsequent work has shown that the expression of the vitamin D receptors is a determinant of insulin secretory capacity in Bangladeshi Asians.
Vitamin D, syndrome 'X', and inflammation
The concepts behind syndrome 'X' are very important because they bring focus to a cluster of related symptoms or disorders that are rapidly becoming a major health concern in Western society. In particular, syndrome X refers to group of health problems that can include type II diabetes, an atherogenic lipoprotein profile, obesity, and high blood pressure. This cluster of disorders is also characterized by increased levels of inflammation, which, in turn, contribute to a variety of chronic diseases such as cardiovascular disease, cancer, Alzheimer's disease, and perhaps premature aging. Boucher (1998) has made a convincing argument that inadequate vitamin D status contributes to syndrome X and that appropriate nutritional and lifestyle changes could help reduce the severity of this syndrome. As detailed above, plasma levels of CRP are very good marker of systemic inflammation. It is significant, therefore, that vitamin D status negatively correlates with plasma CRP levels and that significant reductions in CRP levels occur following vitamin D supplementation (Timms et al., 2002).
Vitamin D, calcium, and heart disease
In a preliminary study of 10 000 women over the age of 65, Varosy (2002) reported that women taking a vitamin D supplement (primarily from multivitamins) lowered their risk from heart disease by 31 per cent. It should be noted that this was a descriptive epidemiological study that did not utilize a randomized, double-blind, placebo-controlled experimental design. There is, however, increasing evidence of a link between CVD and osteoporosis (a gradual loss of bone calcium and increases bone fragility) (Burnett and Vasikaran, 2002). Women with osteoporosis have more calcium in their arterial walls than women with normal bones. In general, the degree of coronary artery calcification correlates very well with the degree of atherosclerotic plaque formation (Arad et al., 1998; Schmermund et al., 1998; Fiorino, 1998). Similarly, Watson et al. (1997) found an inverse correlation between serum 1,25-dihydroxy vitamin D levels and the extent of coronary calcification in 173 subjects with high and moderate risk for coronary heart disease.
It is reasonable to suggest, therefore, that loss of calcium from bones is associated with an increased accumulation of calcium in atherosclerotic plaque and that vitamin D or its metabolites could play a role in this process. Accordingly, Arad et al. (1998) measured serum concentrations of 1,25-dihydroxy vitamin D and the degree of coronary calcification in 50 subjects undergoing angiography. In contrast to the work cited above, these authors found no correlation between serum concentrations of 1,25-dihydroxy vitamin D and coronary calcification or the ratio of coronary calcification to the extent of coronary stenosis (a measure of atherosclerotic plaque formation).
Vitamin D, inflammation, and atherosclerosis
Atherosclerosis is an inflammatory vascular disease mediated by inflammatory cells, cytokines and chemokines. The T-cell plays an important role in mediating atherosclerosis and the effect of vitamin D on T-cell function may be an additional pathway by which this vitamin modulates heart disease. It is interesting, therefore, that 1,25-dihydroxyl vitamin D has been found to inhibit Th1 and Th2 cell differentiation in human cord blood cells (Pichler et al., 2002) and diminish the production of interleukin-2 (IL-2), interferon gamma (IFN-gamma), IL-1, and tumor necrosis factor-alpha (TNF-alpha) in peripheral blood mononuclear cells. The inhibition of Th1 and Th2 cell differentiation and the decreased production of inflammatory cytokines associated with increased serum 1,25-dihydroxy vitamin D suggests an ameliorating effect on atherogenesis (Smith et al., 1999; Krishnaswamy et al., 2002). On the other hand, a recent study from India demonstrated elevated levels of serum 25-dihydroxy vitamin D in South Indian patients with ischemic heart disease, suggesting a pathogenic role in atherosclerosis (Rajasree et al., 2001). Because of these controversies, the actual role of vitamin D in promoting or preventing atherosclerosis is unclear. It is likely that a dose-dependent effect or an age-related effect may by discovered if well-controlled studies are conducted.
Vitamin D nutriture, in addition to playing a potential role in atherosclerosis, may also be an important factor in the pathogenesis of congestive heart failure (Zittermann, 2003; Zittermann et al., 2003). Congestive heart failure (CHF) can have multiple etiologies but is characterized by a reduced amount of blood being pumped from the left ventricle of the heart and, therefore, a reduced amount of blood reaching other organ systems. This disease is often the end stage of cardiac disease and, as more cardiac patients survive their initial problems, the opportunity for developing CHF increases. In aging Western societies, CHF is projected to reach epidemic proportions (http://www.nhlbi.nih.gov/health/ public/heart/other/CHF.htm). Zittermann et al. (2003) have hypothesized that disturbances in calcium homeostasis could play a role in CHF since it is known that calcium plays a key role in the contractility of cardiac muscle. Observational studies have demonstrated an association of vitamin D deficiency in patients with severe CHF (Shane et al., 1997). Zittermann et al. (2003) found that patients with CHF have reduced levels of 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D compared with controls. These authors speculate that low circulating levels of vitamin D metabolites could contribute to the etiology of CHF.
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