Oncotarget | February 16, 2017

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 and Liuzzo G

Oncotarget. 2017;8:17529-17550.

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⁺CD28^nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4⁺CD25^highT-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.