Abstract 13468: The Expression and Role of the A2B Adenosine Receptor in Human Cardiac Myocytes
Background and aims: Adenosine is a signaling nucleoside and its levels are elevated in ischemic myocardium and in plasma of patients with chronic heart failure.
Results of previous studies have shown the A2B adenosine receptor (A2BAdoR) antagonist, GS-6201 significantly improves myocardial infarction-induced cardiac dysfunction and remodeling in mouse and rat. In addition, adenosine has pro-fibrotic effects in human cardiac fibroblasts via activating the A2BAdoR. In the present study we determined the expression level of A2BAdoR in human cardiac myocytes (hCM) and the effect of A2BAdoR activation on release of inflammatory, fibrotic mediators and biomarkers and the downstream molecular mechanisms.
Methods: Gene expression was determined using real-time RT-PCR. The concentrations of IL-6, IL-8, soluble ST-2 and PAPPA in the cell supernatants and levels of phospho-p38 MAPK were measured using ELISA.
Results: Among the four subtypes of AdoRs, the A2BAdoR was expressed at the highest level in primary normal hCM. NECA, a stable analog of adenosine, significantly increased the release of IL-6 and IL-8 in a concentration-dependent manner, with a maximal increase of 6.0±0.3 and 2.4±0.2 fold over the basal level after overnight treatment, respectively. Importantly, NECA increased the release of two novel biomarkers of cardiac tissue injury, soluble ST-2 (4.1±0.2 fold maximal induction) and PAPPA (3.0±0.3 fold maximal induction). The effects of NECA on release of IL-6, IL-8, ST-2, and PAPPA were completely abolished by the selective A2BAdoR antagonist, GS-6201. A2BAdoR-induced IL-6 release was mediated by p38 MAPK. Activation of the A2BAdoR significantly increased phosphorylation of p38 MAPK. Both p38 inhibitors, SB202190 and SB203580 completely abolished NECA’s effect on IL-6 release, whereas the ERK inhibitor PD98059 did not. In addition, activation of the A2BAdoR alters the expression of certain fibrotic genes.
Conclusions: This study indicates that the A2BAdoR is the predominant subtype of AdoRs expressed in primary hCM. Activation of this receptor increases the release of IL-6, IL-8, ST-2 and PAPPA from hCM by activating p38 MAPK. These findings suggest that A2BAdoR might mediate the inflammatory and fibrotic responses in heart diseases.
- © 2012 by American Heart Association, Inc.