RESUMO
Intracoronary stenting is a common procedure in patients with coronary artery disease (CAD). Stent deployment stretches and denudes the endothelial layer, promoting a local inflammatory response, resulting in neointimal hyperplasia. Vitamin D deficiency associates with CAD. In this study, we examined the association of vitamin D status with high mobility group box 1 (HMGB1)-mediated pathways (HMGB1, receptor for advanced glycation end products [RAGE], and Toll-like receptor-2 and -4 [TLR2 and TLR4]) in neointimal hyperplasia in atherosclerotic swine following bare metal stenting. Yucatan microswine fed with a high-cholesterol diet were stratified to receive vitamin D-deficient (VD-DEF), vitamin D-sufficient (VD-SUF), and vitamin D-supplemented (VD-SUP) diet. After 6 months, PTCA (percutaneous transluminal balloon angioplasty) followed by bare metal stent implantation was performed in the left anterior descending (LAD) artery of each swine. Four months following coronary intervention, angiogram and optical coherence tomography (OCT) were performed and swine euthanized. Histology and immunohistochemistry were performed in excised LAD to evaluate the expression of HMGB1, RAGE, TLR2, and TLR4. OCT analysis revealed the greatest in-stent restenosis area in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. The protein expression of HMGB1, RAGE, TLR2, and TLR4 was significantly higher in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. Vitamin D deficiency was associated with both increased in-stent restenosis and increased HMGB1-mediated inflammation noted in coronary arteries following intravascular stenting. Inversely, vitamin D supplementation was associated with both a decrease in this inflammatory profile and in neointimal hyperplasia, warranting further investigation for vitamin D as a potential adjunct therapy following coronary intervention.
Assuntos
Doença da Artéria Coronariana/cirurgia , Proteína HMGB1/metabolismo , Hiperplasia/prevenção & controle , Neointima/prevenção & controle , Intervenção Coronária Percutânea/efeitos adversos , Stents/efeitos adversos , Vitamina D/administração & dosagem , Animais , Doença da Artéria Coronariana/patologia , Feminino , Proteína HMGB1/genética , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Masculino , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Suínos , Vitaminas/administração & dosagemRESUMO
INTRODUCTION: Neointimal hyperplasia (NIH) and restenosis after percutaneous transluminal coronary angioplasty (PTCA) and intravascular stenting remain a problem on a long-term basis by causing endothelial denudation and damage to the intima and media. Vascular sterile inflammation has been attributed to the formation of NIH. Cathepsin L (CTSL), a lysosome protease, is associated with diet-induced atherogenesis. Vitamin D regulates the actions and regulatory effects of proteases and protease inhibitors in different cell types. Objectives of this study are to evaluate the modulatory effect of vitamin D on CTSL activity in post-PTCA coronary arteries of atherosclerotic swine. METHODS: Yucatan microswine were fed with high-cholesterol atherosclerotic diets. The swine were stratified to receive three diets: (1) vitamin D-deficient diet, (2) vitamin D-sufficient diet, and (3) vitamin D-supplement diet. After 6 mo, PTCA was performed in the left circumflex coronary artery (LCx). After 1 y, angiography and optical coherence tomography imaging were performed, and swine was euthanized. Coronary arteries were embedded in paraffin. Tissue sections were stained with hematoxylin and eosin. Expression of Ki67 and CTSL were evaluated by immunofluorescence. RESULTS: Increased number of Ki67 + cells were observed in the postangioplasty LCx in vitamin D-deficient compared with vitamin D-sufficient or vitamin D-supplemented swine. Notably, the expression of CTSL was significantly increased in postangioplasty LCx of vitamin D-deficient swine compared with the vitamin D-sufficient or vitamin D-supplemented animal groups. CONCLUSIONS: Increased expression of CTSL correlates with the formation of NIH in the PTCA-injured coronary arteries. However, in the presence of sufficient or supplemented levels of vitamin D in the blood, CTSL expression was significantly reduced.
Assuntos
Catepsina L/metabolismo , Vasos Coronários/efeitos dos fármacos , Neointima/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/uso terapêutico , Angioplastia Coronária com Balão/efeitos adversos , Animais , Aterosclerose/terapia , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/etiologia , Vasos Coronários/metabolismo , Suplementos Nutricionais , Feminino , Fator de Crescimento Insulin-Like I , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Neointima/prevenção & controle , Suínos , Tomografia de Coerência Óptica , Fator de Necrose Tumoral alfa/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/prevenção & controleRESUMO
Vitamin D functions as a potent immunomodulator by interacting with many immune cells however, its role in regulating inflammation in the epicardial adipose tissue (EAT) is unclear. In the EAT of atherosclerotic microswine that were fed with deficient, sufficient or supplemented levels of vitamin D, we evaluated the phenotype of the macrophages. Vitamin D treatment was continued for 12 months and serum 25(OH)D levels were measured regularly. Infiltration of M1/M2 macrophage was investigated by immunostaining for CCR7 and CD206, respectively in conjunction with a pan macrophage marker CD14. Significant difference in the number of CCR7+ cells was observed in the EAT from vitamin D-deficient swine compared to vitamin D-sufficient or -supplemented swine. Expression of CD206 correlated with high levels of serum 25(OH)D indicating a significant increase in M2 macrophages in the EAT of vitamin D-supplemented compared to -deficient swine. These findings suggest that vitamin D-deficiency exacerbates inflammation by increasing pro-inflammatory M1 macrophages, while vitamin D-supplementation attenuates the inflammatory cytokines and promotes M2 macrophages in EAT. This study demonstrates the significance of vitamin D mediated inhibition of macrophage mediated inflammation in the EAT during coronary intervention in addition to its immunomodulatory role. However, additional studies are required to identify the cellular mechanisms that transduce signals between macrophages and smooth muscle cells during restenosis in the presence and absence of vitamin D.