Decreased Expression of Vitamin D Receptors in Neointimal Lesions following Coronary Artery Angioplasty in Atherosclerotic Swine
Decreased Expression of Vitamin D Receptors in Neointimal Lesions following Coronary Artery Angioplasty in Atherosclerotic Swine
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DOI：
10.1371/journal.pone.0042789
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发表时间：
2012-08-06
期刊：
影响因子：
3.7
通讯作者：
Agrawal, Devendra K.
中科院分区：
文献类型：
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作者：
Gupta, Gaurav K.;Agrawal, Tanupriya;Agrawal, Devendra K.
背景：炎症细胞因子，如 TNF-α，在闭塞性血管疾病的发病机制中发挥着关键作用。维生素 D 受体 (VDR) 的激活会引起生长抑制和抗炎作用。在这里，我们研究了高胆固醇血症猪血管成形术后冠状动脉新生内膜病变中 TNF-α 和 VDR 的表达，并检查了维生素 D 缺乏对冠状动脉再狭窄发展的影响。我们还体外研究了骨化三醇对细胞增殖的影响以及 TNF-α 对猪冠状动脉平滑肌细胞 (PCASMC) 中 VDR 活性和表达的影响。方法学/主要发现：通过免疫组织化学和组织形态计量学分析血管成形术后冠状动脉中 VDR 和 TNF-α 的表达以及维生素 D 缺乏的影响。在培养的 PCASMC 中通过胸苷和 BrdU 掺入测定检查细胞增殖。通过荧光素酶测定、免疫印迹和免疫细胞化学分析TNF-α刺激对VDR活性和表达的影响。体内组织的形态测量分析揭示了具有显着新内膜增殖的典型病变。组织学评估显示新内膜病变中平滑肌α-肌动蛋白的表达和TNF-α的表达显着增加。有趣的是，与正常介质相比，新内膜区域的PCASMC中VDR的表达显着降低。事实上，与维生素 D 充足的组相比，缺乏维生素 D 的高胆固醇血症猪的球囊血管成形术后再狭窄明显更高。在体外，骨化三醇抑制血清和 PDGF-BB 诱导的 PCASMC 增殖，并且 TNF-α 刺激显着降低 PCASMC 中 VDR 的表达和活性。 结论/意义：这些数据表明，新内膜病变中增殖的平滑肌细胞中 VDR 的显着下调可能是由于致动脉粥样硬化细胞因子，包括 TNF-α。维生素 D 缺乏会加剧冠状动脉再狭窄的发生。骨化三醇在 PCASMC 中具有抗增殖特性，这些作用是通过 VDR 介导的。这可能是受伤动脉中新内膜细胞不受控制生长导致再狭窄的潜在机制。
Background: Inflammatory cytokines, such as TNF-alpha, play a key role in the pathogenesis of occlusive vascular diseases. Activation of vitamin D receptors (VDR) elicits both growth-inhibitory and anti-inflammatory effects. Here, we investigated the expression of TNF-alpha and VDR in post-angioplasty coronary artery neointimal lesions of hypercholesterolemic swine and examined the effect of vitamin D deficiency on the development of coronary restenosis. We also examined the effect of calcitriol on cell proliferation and effect of TNF-alpha on VDR activity and expression in porcine coronary artery smooth muscle cells (PCASMCs) in-vitro.Methodology/Principal Findings: Expression of VDR and TNF-alpha and the effect of vitamin D deficiency in post-angioplasty coronary arteries were analyzed by immunohistochemistry and histomorphometry. Cell proliferation was examined by thymidine and BrdU incorporation assays in cultured PCASMCs. Effect of TNF-alpha-stimulation on the activity and expression of VDR was analyzed by luciferase assay, immunoblotting and immunocytochemistry. In-vivo, morphometric analysis of the tissues revealed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle alpha-actin and significantly increased expression of TNF-alpha in neointimal lesions. Interestingly, there was significantly decreased expression of VDR in PCASMCs of neointimal region compared to normal media. Indeed, post-balloon angioplasty restenosis was significantly higher in vitamin D-deficient hypercholesterolemic swine compared to vitamin D-sufficient group. In-vitro, calcitriol inhibited both serum- and PDGF-BB-induced proliferation in PCASMCs and TNF-alpha-stimulation significantly decreased the expression and activity of VDR in PCASMCs.Conclusions/Significance:These data suggest that significant downregulation of VDR in proliferating smooth muscle cells in neointimal lesions could be due to atherogenic cytokines, including TNF-alpha. Vitamin D deficiency potentiates the development of coronary restenosis. Calcitriol has anti-proliferative properties in PCASMCs and these actions are mediated through VDR. This could be a potential mechanism for uncontrolled growth of neointimal cells in injured arteries leading to restenosis.