Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional pro of CD4+T-lymphocytes in acute coronary syndromes

• Published in: Oncotarget Vol. 8; no. 11; pp. 17529 - 17550
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Impact Journals LLC 16.02.2017
• Subjects: Research Paper: Pathology
• ISSN: 1949-2553
• 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 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 + CD28 null T-cells ( P = 0.009) and a significant increase in interleukin-10-producing CD4 + CD25 high T-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.