Page 143 - Vitamin D and Cancer

130 R. Scragg

Physiological changes
Decreased matrix-metallo-proteases
vitamin D endothelial dysfunction ( NO)
insulin resistance
renin-angiotensin
adverse immune function

Disease
coronary heart disease Pathological changes
stroke cardiac hypertrophy
congestive heart failure arterial resistance
peripheral vascular disease plaque formation & rupture
hypertension thrombosis

Fig. 6.2 Mechanisms by which low vitamin D status may increase the risk of cardiovascular
disease

excesses in CV disease that coincided with winter respiratory infections (see
Sect. 6.3.1). Opinion has changed substantially over the last 10 years, and it is now
well established that subclinical inflammatory factors mediate the traditional
chronic risk factors (such as smoking) and are centrally involved in the process of
atherosclerosis and plaque rupture [162–164]. Blood levels of inflammatory mark-
ers, such as C-reactive protein (CRP) and the cytokine interleukin-6 (IL-6), predict
subsequent risk of cardiovascular disease [164, 165]. Inflammatory cytokines also
influence endothelial function [165, 166], which is an independent predictor of CV
disease [167], and synthesis of MMPs [168] which also have a role in CV disease
[169, 170]; while positive associations have been reported between IL-6 and insulin
resistance [171–173] which are consistent with a role for pro-inflammatory factors
in the etiology of type 2 diabetes [174, 175].
In a recent landmark paper, vitamin D was shown to have an important role in
the innate immune system by stimulating the synthesis of the antimicrobial peptide
cathelicidin [176]. This new finding provides a biological explanation for the his-
torical link between sun exposure, vitamin D, and tuberculosis [177], as well as the
association between rickets and infection which has been known since the 1960s
[178]. Further, subclinical vitamin D deficiency has been reported in newborns and
young adults without rickets, suffering from acute respiratory infections [179, 180],
while women receiving vitamin D supplements in a clinical trial reported fewer
respiratory symptoms than controls [181].
Laboratory in vitro studies have shown that 1,25(OH) D decreases production
3
2
of pro-inflammatory cytokines such as IL-6 and tumor necrosis factor a (TNFa) by
macrophages and lymphocytes[182–184] and up-regulates synthesis of anti-
inflammatory IL-10 [185]. However, human studies of vitamin D supplementation
have produced conflicting results perhaps due to varying doses of vitamin D.
Vitamin D supplementation (2,000 IU/day for 9 months) decreased TNFa and