Abstract 031: β-Adrenergic Receptor-Mediated Transactivation Of Epidermal Growth Factor Receptor Decreases Cardiomyocyte Apoptosis Through Differential Activation Of ERK1/2 and Akt
β-adrenergic receptors (βAR) are critical regulators of cardiac function whose dysregulation during heart failure are associated with diminished function. However, βAR-mediated EGFR transactivation has been shown to relay cardioprotection in a mouse model of heart failure via unknown mechanisms. We hypothesized that transactivation of EGFR promotes survival via distinct cardiomyocyte signaling responses leading to decreases in apoptosis. To test this hypothesis, C57BL/6 mice were injected with isoproterenol (Iso) in the presence or absence of the EGFR antagonist AG1478 and ERK1/2 and Akt phosphorylation and subcellular distribution were assessed. Following 10 min Iso stimulation, increases in ERK1/2 and Akt phosphorylation were observed in cytosolic, plasma membrane and nuclear fractions. Phosphorylation of ERK1/2 were AG1478 sensitive in all three fractions while Akt phosphorylation occurred through EGFR-transactivation only in plasma membrane and nuclear fractions, which was confirmed in rat neonatal cardiomyocytes (RNCM). Additionally, EGFR-transactivation by βAR decreased apoptosis, as measured via caspase 3 activation/activity and TUNEL assay, which was sensitive to inhibition of both ERK1/2 and Akt signaling pathways. Increased phosphorylation of ERK1/2 and Akt in the nucleus and the ability to inhibit Iso-mediated changes in apoptosis with the transcriptional inhibitor Actinomycin D suggested that the cardioprotective effects of Iso-mediated EGFR transactivation may be influenced by changes in gene transcription. An Apoptotsis RT2 PCR Array was used to identify changes in transcript levels of 84 apoptotic genes. Of these, 12 were found to be altered in response to EGFR inhibition in the presence of Iso. These results demonstrate that βAR-mediated EGFR transactivation in the heart induces differential subcellular activation of ERK1/2 and Akt and leads to the promotion of cell survival, in part through the modulation of apoptotic gene expression in cardiomyocytes. Further understanding the downstream consequences of these effects in response to βAR-mediated EGFR transactivation could lead to improved therapies for the treatment of heart failure.
- © 2013 by American Heart Association, Inc.