Abstract 12488: Spontaneous Beating of Cardiac Pacemaker Cells is Regulated by Basal Activation of Epidermal Growth Factor Receptor
Spontaneous firing of sinoatrial node cells (SANC) is controlled by sarcoplasmic reticulum (SR) generated local subsarcolemmal Ca2+ releases (LCRs), which appear during diastolic depolarization (DD) and activate an inward Na+-Ca2+exchange current to regulate DD rate and spontaneous SANC beating rate. Therapy directed against the epidermal growth factor receptor (EGFR) pathway had improved outcomes for patients with different types of cancer. It was noted, however, that inhibition of EGFR might lead to sinus bradycardia and sick sinus syndrome. Until now neither expression nor possible role of EGFR for spontaneous beating of cardiac pacemaker was examined. Here we studied expression of EGFR in rabbit SANC; effects of EGFR inhibition on spontaneous SANC firing and possible mechanisms of EGFR-dependent regulation of cardiac pacemaker function.
We discovered that expression of EGFR (RNA-sequencing) in rabbit SANC exceeded that in ventricular myocytes by six-fold. Specific EGFR inhibitors erlotinib and AG1478 markedly decreased spontaneous SANC beating rate (perforated patch-clamp technique) and this effect was largely reversible upon drug washout. Both erlotinib and AG1478 suppressed SR Ca2+ cycling (confocal microscopy, Ca2+indicator Fluo-3) in SANC, i.e. decreased LCR size and number per each spontaneous cycle and prolonged the LCR period (the interval between AP-induced Ca2+ transient and subsequent LCR), which predicted the concomitant increase in the spontaneous cycle length. These data indicate basal activation of EGFR, which could activate other kinase cascades in rabbit SANC e.g. PKC-dependent phosphorylation through activation of PLC. Inhibition of either PLC activity by U-73122 or PKC activation by GF109203X or calphostin C suppressed LCRs and stopped spontaneous firing of rabbit SANC. We conclude that basal activation of EGFR regulates cardiac pacemaker function through PLC-PKC-dependent modulation of LCR characteristics. This might represent a novel pathway to control normal automaticity of SANC, which could be affected by cancer treatment therapy.
Author Disclosures: T.M. Vinogradova: None. K.V. Tarasov: None. E.G. Lakatta: None.
- © 2015 by American Heart Association, Inc.