Abstract
Vitamin D is a fat-soluble steroid hormone that activates vitamin D receptor to regulate multiple downstream signaling pathways and transcription of various target genes. There is an association between vitamin D deficiency and increased risk for cardiovascular disease. However, most of the studies are observational and associative in nature with limited data on clinical application. Thus, there is a need for more prospective randomized controlled studies to determine whether or not vitamin D supplementation provides cardiovascular protection. In this study, we examined the effects of the deficiency and supplementation of vitamin D on coronary restenosis following coronary intervention in atherosclerotic Yucatan microswine. Twelve Yucatan microswine were fed vitamin D-deficient (n = 4) or -sufficient (n = 8) high cholesterol diet for 6-months followed by coronary intervention. Post-intervention, swine in the vitamin D-sufficient high cholesterol diet group received daily oral supplementation of either 1,000 IU (n = 4) or 3,000 IU (n = 4) vitamin D3. Six months later, optical coherence tomography (OCT) was performed to monitor the development of intimal hyperplasia and restenosis. Animals were euthanized to isolate arteries for histomorphometric and immunohistochemical studies. Animals had graded levels of serum 25(OH)D; vitamin D-deficient (15.33 ± 1.45 ng/ml), vitamin D-sufficient + 1,000 IU oral vitamin D post-intervention (32.27 ± 1.20 ng/ml), and vitamin D-sufficient + 3,000 IU oral vitamin D post-intervention (51.00 ± 3.47 ng/ml). Findings from the OCT and histomorphometric studies showed a decrease in intimal hyperplasia and restenosis in vitamin D-supplemented compared to vitamin D-deficient swine. Vitamin D supplementation significantly decreased serum levels of TNF-α and IFN-γ, upregulated serum levels of IL-10, and had no effect on serum IL-6 levels. These findings suggest that vitamin D supplementation limits neointimal formation following coronary intervention in atherosclerotic swine and provide the support for vitamin D supplementation to protect against the development of coronary restenosis.
Highlights
Coronary artery disease (CAD), the most common among cardiovascular diseases, is a primary cause of morbidity and mortality in the developed world and predicted to remain so for the 20 years [1]
Since all swine were kept in the controlled environment, there was an initial decrease in the serum levels of 25(OH)D due to controlled diet and dark conditions
High cholesterol diet induced the severe hypercholesterolemia in all animals with no significant differences in total serum cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels between the groups (Fig 1C–1E)
Summary
Coronary artery disease (CAD), the most common among cardiovascular diseases, is a primary cause of morbidity and mortality in the developed world and predicted to remain so for the 20 years [1]. Stents coated with anti-proliferative and anti-inflammatory agents, “drug-eluting” stents (DESs), have been used to prevent restenosis Despite all of these benefits, the safety of DES has been called into question by recent studies, suggesting that DES could produce adverse arterial responses, including delayed endothelialization and hypersensitivity to the polymeric coating responsible for the regulation of drug dosing and release kinetics [7,8,9,10]. Macrophages, vascular smooth muscle cells (VSMCs) and endothelial cells produce inflammatory cytokines [13,14,15] involved in the process of atherosclerosis These cytokines include tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6, which induce the inflammatory response, cell proliferation and apoptosis, and leading to the pathogenesis of restenosis following PTCA
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