VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE

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DESCRIPTION (provided by applicant): Increased prevalence of coronary artery disease is very high and almost 50% of elderly population of the world is vitamin D-deficient. Low levels of vitamin D have increased risks of heart disease, stroke, hypertension, and diabetes. The incidence of angiographic restenoses following balloon angioplasty/stent implantation correlates well with the incidence of vitamin D deficiency/insufficiency. There is no data to predict which patient will develop intimal hyperplasia and in-stent restenosis following coronary intervention. The purpose of this study is to evaluate the effect of vitamin D status on the outcome measures of coronary patency following intervention in a well-controlled swine model of atherosclerosis and to determine the underlying cellular and molecular mechanisms. The central hypothesis is that intimal hyperplasia after coronary intervention depends on vitamin D status and supplementation with vitamin D inhibits inflammation. We propose to utilize a hyperlipidemic and atherosclerotic microswine model fed with vitamin D-deficient, vitamin D-sufficient, and vitamin D-supplemented diet. Animals will undergo balloon angioplasty or intravascular stenting. The hypothesis in Aim 1 predicts that vitamin D deficiency will increase intimal hyperplasia and restenosis following coronary artery intervention by increasing smooth muscle cell proliferation (SMC) and enhancing inflammation. The hypothesis in Aim 2 predicts that vitamin D supplementation will decrease intimal hyperplasia and restenosis following coronary artery intervention by decreasing SMC proliferation and inhibiting inflammation. The hypothesis of Aim 3 predicts that vitamin D decreases intimal hyperplasia and restenosis by inhibiting inflammation and decreasing smooth muscle cell proliferation by decreasing translocation of NF-kB to the nucleus via inhibition of transcription and translation of importin-¿3. Hypercholesterolemic and atherosclerotic microswine with vitamin D deficiency, sufficiency and supplementation will be followed over a period of six months following coronary intervention with left ventriculogram and optical coherence tomography to assess cardiac function and quantify in-segment minimal luminal diameter, diameter stenosis, late loss and intimal hyperplasia. Also, serum levels of 25-hydroxyvitamin D, inflammatory mediators and cytokines, lipid profile and other biochemical and clinical variables. Histological and immunohistochemical evaluation of coronary arteries for intimal thickness, intimal hyperplasia, lumen area, intima-media ratio, plaque development and plaque ulceration, and re-occlusion, and infiltration of inflammatory cells will be performed. Also the mRNA and protein expression of VDR, CYP24A1, CYP27B1, NF-kB, importin-¿3, and prohibitin in isolated smooth muscle cells will be examined. These studies will provide the conceptual support of our hypothesis and position us to assess the effectiveness of vitamin D supplementation in the prevention of clinical complications following coronary interventions in patients with coronary artery disease.