ReviewProtective and toxic effects of vitamin D on vascular calcification: Clinical implications
Introduction
Life expectancy is increasing worldwide. Nevertheless, the burden of cardiovascular disease (CVD) morbidity and mortality is still high in developed countries and is rapidly increasing in developing countries (Yusuf et al., 2001). Several risk factors for CVD have been identified in the past. But classical risk factors such as smoking, dyslipoproteinemia, hypertension, and disturbed glucose metabolism can not completely explain the high prevalence of CVD. Until recently, vascular calcification (VC) was considered to be a passive process that occurred as a non-specific response to vascular damage without clinical significance. However, evidence is now accumulating that VC is an active process (see below). VC can cause thrombosis, arterial rupture and myocardial infarction (Grasse et al., 2007). The presence of VC is a predictor of poorer 5-year survival in the general population (Margolis et al., 1980). VC must thus be regarded as an important risk factor for CVD mortality.
During the last decade it also became clear that deficient vitamin D status is a worldwide problem (Zittermann, 2006). The by far most important reason for this phenomenon is an inadequate skin exposure to solar ultraviolet B radiation, since ultraviolet B-induced skin synthesis is the major source of vitamin D for humans. Some clinical studies have reported cross-sectional associations between lower vitamin D levels and prevalent CVD. In addition, ecological studies have reported higher rates of coronary heart disease and hypertension with increasing distance from the equator, a phenomenon that can be attributed to the higher prevalence of vitamin D deficiency in regions with less exposure to sunlight (Zittermann et al., 2005).
It has long been known that vitamin D plays a major role in bone mineral homeostasis by promoting the transport of calcium and phosphate to ensure adequate blood levels of these ions for normal bone mineralization. Bone diseases such as rickets, osteomalacia, and osteoporosis are well-known consequences of vitamin D deficiency in infants and adults, respectively. It is now well established that there is an inverse relationship between osteoporosis and the degree of VC (Banks et al., 1994, Barengolts et al., 1998) indicating that VC occurs when there is a net calcium efflux from bone. However, experimental studies and human case reports also indicate that supra-physiological amounts of vitamin D can lead to VC. This review article therefore summarises the molecular basis of protective and toxic vitamin D effects on the vasculature. Moreover, the clinical implications resulting from the association of VC with vitamin D deficiency are outlined.
Section snippets
The vitamin D endocrine system
Vitamin D can be ingested orally or can be synthesized in the human skin by the solar ultraviolet B spectrum. Usually, dietary vitamin D contributes only 10–20% to human vitamin D supply. In the human body, cutaneously synthesized or orally ingested vitamin D is metabolized by a hepatic hydroxylase into 25-hydroxyvitamin D(25(OH)D) and by a renal 1α-hydroxylase into the vitamin D hormone 1,25-dihydroxyvitamin D (calcitriol) (Fig. 1). Due to its chemical structure, calcitriol must be regarded as
Mechanisms
VC can be categorized into atherosclerotic intimal calcification, medial artery calcification, and valvular calcification. VC is an actively regulated process. In general, the development of tissue calcification requires a pre-existing injury as an inducer, whereas further progression requires the presence of other promoter factors such as hyperphosphatemia and hypercalcemia and/or a deficiency in calcification repressor factors (Grasse et al., 2007). Intimal artery calcification is associated
Chronic kidney disease as a human model for vascular calcification
In patients with chronic kidney disease (CKD), both VC and calcitriol deficiency are extremely common. Serum concentrations of calcitriol already decrease when renal function impairs (Juttmann et al., 1981). Activity of renal 1α-hydroxylase is attenuated due the decreased number of viable nephrons as well as to phosphate load (Fukagawa and Kurokawa, 2005). Serum calcitriol levels decline already in the presence of normal calcium and phosphate levels (Levin et al., 2007). There is some evidence
Vitamin D receptor activation and clinical outcome in patients with chronic kidney disease
Solely in the US, CKD affects as many as 19 million adults, with 20 million more at risk. More than 6 million Americans have significant reductions in kidney function, and nearly 400,000 require dialysis to prevent death (Joy et al., 2007). Therefore, effective treatment of CKD is of great medical and socioeconomic interest. It seems logical to treat CKD with active vitamin D such as calcitriol (1,25-dihydroxyvitamin D3), 1α-vitamin D3, or doxercalciferol (1α-vitamin D2). However, treatment of
Future perspectives
The effects of supra-physiological vitamin D dosages on VC are now well characterized in experimental animals. In addition, several animal models are now available to study ablation of specific genes on VC. However, data on VC in vitamin D deprived animals or in animals with absent vitamin D action are almost completely lacking.
The vasculature seems to be an important target tissue for vitamin D. The fact that VSMCs express a 1α-hydroxylase that is regulated by PTH raises further questions: Is
Summary
The steroid hormone calcitriol exerts important biological actions via membrane-bound and/or cytosolic receptors in almost all human cells and tissues. There is increasing evidence that physiologic vitamin D concentrations are associated with a low risk of VC and low mortality. VC is an active process and both vitamin D deficiency and vitamin D intoxication seem to be involved in this process indicating that there is a bimodal association of vitamin D with VC. CKD is a disease that is
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2020, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :Further, a recent trial in swine found that high calcium diets (up to 2000 mg a day) had no detectable effect on coronary artery calcium deposition [40], and vitamin D intakes reaching at an extremely high serum 25[OH]D concentration (such as > 375 nmol/L) can be detrimental [41]. Renal function may also play a role, as kidneys are involved in the metabolism of vitamin D [38,42]. Although a close association of kidney disease with hypovitaminosis D has been suggested [43,44], in people without chronic kidney disease, the high concentration of inactive forms of vitamin D was found to be associated with the reduction of estimated renal function [45].