Severino Anna, Zara Chiara, Campioni Mara, Flego Davide, Angelini Giulia, Pedicino Daniela, Giglio Ada Francesca, Trotta Francesco, Giubilato Simona, Pazzano Vincenzo, Lucci Claudia, Iaconelli Antonio, Ruggio Aureliano, Biasucci Luigi Marzio, Crea Filippo, Liuzzo Giovanna
Institute of Cardiology, Catholic University, Rome, Italy.
Oncotarget. 2017 Mar 14;8(11):17529-17550. doi: 10.18632/oncotarget.15420.
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 μg/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-γ-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.
背景 - 适应性免疫反应与急性冠状动脉综合征的不良预后相关。他汀类药物除了降低血脂水平外还具有抗炎活性。我们研究了急性冠状动脉综合征中阿托伐他汀体外和体内治疗对CD4 + T细胞的影响及其潜在分子机制。
方法与结果 - 从50名未服用他汀类药物的急性冠状动脉综合征患者中采集血样。在与递增剂量的阿托伐他汀（3 - 10 - 26μg/ml，分别对应于10 - 40 - 80mg剂量所达到的血药浓度）孵育24小时前后，我们通过流式细胞术评估CD4 + T细胞活化，通过RT - qPCR评估84种辅助性T细胞转录因子和84种T细胞相关基因的表达，并通过蛋白质印迹法评估蛋白质表达。孵育后，我们发现产生干扰素 - γ的CD4 + CD28nullT细胞显著减少（P = 0.009），而产生白细胞介素 - 10的CD4 + CD25highT细胞显著增加（P < 0.001）。阿托伐他汀增加了2个基因的表达并降低了12个基因的表达（特别是EGR1、FOS、CCR2和Toll样受体 - 4；变化超过3倍）。在10名未服用他汀类药物的急性冠状动脉综合征患者中分析了阿托伐他汀的体内作用，在基线时以及阿托伐他汀治疗（80mg/天）24小时和48小时后：EGR1基因表达在24小时时降低（P = 0.01），在48小时时降低（P = 0.005）；EGR1蛋白水平在48小时时降低（P = 0.03）。
结论 - 在急性冠状动脉综合征中，阿托伐他汀对免疫系统的作用可能部分与主调节基因EGR1的抑制有关。我们的发现可能为他汀类药物改善急性冠状动脉综合征早期预后提供因果解释。
