Abstract 17111: Defective Activation of Transcription Factor CREB in Circulating CD4+ T-cells Might Explain the Reduced Anti-inflammatory Activity in Patients with Acute Coronary Syndrome
Background. Recent studies have highlighted the importance of T-cell disregulation in acute coronary syndromes (ACS). Cyclic-AMP response element binding protein (CREB) is a crucial transcription factor downstream of T Cell Receptor (TCR) signaling that differentially regulates proliferation, survival and differentiation of helper T-cell subsets. CREB is also involved in regulatory T-cell generation and maintenance. We aim to evaluate CREB activation after TCR-stimulation, in CD4+T-cells of patients with ACS compared to patients with chronic stable angina (SA) and healthy controls (HC).
Methods and Results. Consecutive patients with Non-ST elevation ACS (n=10), SA (n=10) and HC ( n=10) were enrolled. After TCR-stimulation with anti CD3/CD28 monoclonal antibody, T-cells were fixed at different time point. CREB phosphorylation at its transcription activating site, serine 133, was analyzed in CD4+T-cells by phosphoflow. Total CREB was assessed by western blot. Results are expressed as fold-changes in TCR-mediated CREB phosphorylation respect to baseline (mean±SE). In ACS, CD4+T-cells showed a reduced CREB activation as compared to SA and HC, after 2’ of TCR-stimulation (1.19±0.08 vs 1.66±0.17 and 2.57±0.37, respectively; P<0.05 ACS vs SA and P<0.001 ACS vs HC) that was still observed after 5’ (1.52±0.09 vs 1.98±0.23 and 3.02±0.36, respectively; P<0.001 ACS vs HC). Also, CREB activation was lower in SA vs HC, both at 2’ and 5’ (P<0.05) (Figure). The amount of total CREB was similar in the three groups at any time.
Conclusions. In ACS, circulating CD4+T-cells exhibited a reduced activation of CREB, a transcription factor downstream of TCR-signaling that mainly promotes anti-inflammatory immune responses. These findings might explain the impaired control of inflammation in ACS, opening novel therapeutic strategies.
- © 2012 by American Heart Association, Inc.