Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes.
Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes.
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亚精胺与运动相结合，通过 AMPK-FOXO3a 信号增强自噬并减少细胞凋亡，从而挽救 D-gal 诱导的衰老大鼠骨骼肌萎缩
DOI：
10.18632/oncotarget.15420
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发表时间：
2017-03-14
期刊：
影响因子：
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通讯作者：
Liuzzo G
中科院分区：
文献类型：
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作者：
Severino A;Zara C;Campioni M;Flego D;Angelini G;Pedicino D;Giglio AF;Trotta F;Giubilato S;Pazzano V;Lucci C;Iaconelli A;Ruggio A;Biasucci LM;Crea F;Liuzzo G
背景-适应性免疫反应与急性冠状动脉综合征较差的预后相关。他汀类药物除了降低血脂水平外还有消炎作用。我们研究了急性冠脉综合征患者体内和离体阿托伐他汀治疗对CD4+ t细胞的影响及其潜在的分子机制。方法和结果-采集了50例statin-naïve急性冠状动脉综合征患者的血液样本。我们通过流式细胞术评估CD4+ t细胞活化，通过RT-qPCR评估84个t辅助转录因子和84个t细胞相关基因的表达，并通过Western-blot评估在阿托伐他汀增加剂量（3-10-26 g/ml，分别对应于10-40-80 mg剂量）24小时培养前后的蛋白表达。孵育后，我们发现干扰素-？产生CD4+ cd28null细胞（P = 0.009）和产生白细胞介素-10的CD4+ cd25high细胞显著增加（P < 0.001）。阿托伐他汀增加了2个基因的表达，降低了12个基因的表达（尤其是EGR1、FOS、CCR2和toll like receptor-4； >3倍变化）。对10例无阿托伐他汀急性冠脉综合征患者在基线时、阿托伐他汀治疗24h和48h （80mg /d）后的体内效应进行分析：egr1基因表达在24h （P = 0.01）和48h （P = 0.005）降低；48h时egr1蛋白水平降低（P = 0.03）。结论：在急性冠脉综合征中，阿托伐他汀对免疫系统的影响可能与抑制主调控基因EGR1有关。我们的发现可能为他汀类药物改善急性冠状动脉综合征的早期结局提供一个因果解释。
Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms. Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 g/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-?-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes). The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03). Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.