Research Papers: Pathology:
Atorvastatin inhibits the immediateearly response gene EGR1 and improves the functional profile of CD4+Tlymphocytes in acute coronary syndromes
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Anna Severino1,*, Chiara Zara1,*, Mara Campioni1, Davide Flego1, Giulia Angelini1, Daniela Pedicino1, Ada Francesca Giglio1, Francesco Trotta1, Simona Giubilato1, Vincenzo Pazzano1, Claudia Lucci1, Antonio Iaconelli1, Aureliano Ruggio1, Luigi Marzio Biasucci1, Filippo Crea1,** and Giovanna Liuzzo1,**
1 Institute of Cardiology, Catholic University, Rome, Italy
* These authors have contributed equally to this work
** These authors have contributed equally to this work
Correspondence to:
Giovanna Liuzzo, email:
Keywords: acute coronary syndromes; T-lymphocytes; transcription factors; statins; inflammation; Pathology Section
Received: December 08, 2016 Accepted: February 07, 2017 Published: February 16, 2017
Abstract
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.