P. Gunasekar1, J. Dabestani1, D. K. Agrawal1, J. A. Asensio1 1Creighton University Medical Center,Department Of Surgery, Div. Trauma Surgery, Department Of Clinical & Translational Science,Omaha, NE, USA
Introduction:
Coronary angioplasty and stent implantation is a common coronary procedure for patients with coronary artery disease. These interventional procedures stretch and denude the endothelial layer. This promotes local inflammatory response in the injured vessel wall, which is characterized by smooth muscle cell proliferation, migration, neointimal formation. Clinical studies support that plasma vitamin D deficiency is associated with increased risk for coronary artery disease (CAD). It is unclear whether vitamin D status is causally related to CAD or is a marker of health. In this study, we examined the inflammatory profile of coronary arteries in atherosclerotic swine.
Methods:
Yucatan microswine were fed with high cholesterol atherosclerotic diet. The swine received approximately 500 IU of vitamin D3/per day on the vitamin D-deficient diet (VD DEF.), 2,500-3,500 IU of vitamin D3/per day on vitamin D-sufficient diet (VD SUF.), and 4,500-5,500 IU of vitamin D3/per day on the vitamin D-supplement diet (VD SUP.). After 5-6 months of the experimental diet, PTCA (percutaneous transluminal balloon angioplasty) was performed in the left circumflex coronary artery (LCX) and bare mental stent implantation in the left anterior descending coronary artery (LAD) for each swine. Six months following coronary intervention, angiogram and optical coherence tomography (OCT) imaging were performed and swine were euthanized. Coronary arteries were then embedded in methyl methacrylate or paraffin. Tissue sections were stained with H&E. The protein expression of HMGB1 (inflammation and necrosis marker), RAGE (receptor for advanced glycosylation end product), TLR2 and TLR4 (pattern recognition receptors) were evaluated by Immunohistochemistry.
Results:
Optical coherence tomography readings showed the degree of percentage area in-stent restenosis and PTCA was greatest in VD DEF. compared to VD SUF. or VD SUP. swine. We found a greater inflammatory profile in the coronary arteries of VD DEF. compared to VD SUF. or VD SUP. swine, based on histological staining and immunoreactivity to HMGB1, RAGE, TLR2, TLR4, in both LCX and LAD. The ligands for RAGE and receptor for HMGB1 (TLR2 and TLR4) were highly expressed in neointimal cells in stented LAD arteries of VD DEF. swine. This inflammatory profile decreases with increasing the levels of Vitamin D.
Conclusion:
Vitamin D deficiency increases the HMGB1-mediated pathways, resulting in the release of inflammatory cytokines from macrophages and other immune cells; and the recruitment of inflammatory cells through TLR4. Vitamin D supplementation suppresses the cytokine activity and prevents neointimal proliferation and restenosis from damage caused by PTCA in atherosclerotic swine. Vitamin D supplementation could be used as an adjunct therapy to prevent intimal hyperplasia and restenosis following coronary interventions.