Abstract 5310: Homeodomain Transcription Factor Irx5 is Necessary for Maintaining Cardiac Contractility and Hypertrophic Response of the Heart to Pressure-Overload
The homeodomain transcription factor, Irx5, negatively regulates KV4.2 expression in the heart, forming an inverse transient outward K+ current (Ito,f) gradient from epicardium (EPI) to endocardium (ENDO) that ensures coordinated cardiac repolarization. Loss of Irx5 in mice (i.e. Irx5−/−) eliminated the KV4.2 and Ito,f gradients, leading to increased susceptibility to tachyarrhythmias. To further investigate the cardiac role of Irx5, we examined the contractile properties of Irx5−/− mouse heart. Compared to control, Irx5−/− hearts displayed lower cardiac contractility as measured either in in vivo or in isolated Langendorff perfused hearts. Consistent with previous studies showing that Ito,f levels regulate Ca2+ entry and contractility via modulation of action potential (AP) profile, we observed that isolated ENDO ventricular myocytes from Irx5−/− had reduced cell shortening and [Ca2+]i transients along with increased Ito,f and abbreviated AP durations compared to control. By contrast, Ito,f, AP profile, myocyte contractility and [Ca2+]i transients in EPI myocytes from Irx5−/− were indistinguishable from either control EPI myocytes or Irx5−/− ENDO myocytes. Despite the low contractility, hypertrophy was not observed in Irx5−/− hearts. To explore whether reduced contractility in Irx5−/− heart might affect a response to disease, we subjected mice to pressure-overload by transverse aortic constriction (TAC). In spite of applying the same degree of constriction, TAC-Irx5−/− mice exhibited lower (P < 0.05) systolic arterial and ventricular pressures along with decreased (P < 0.05) cardiac output compared to TAC-Irx5+/+. In addition, 2 and 8 weeks after TAC, cardiac hypertrophy was lower (P < 0.01) while the extent of cardiac dilation at 8 week post-TAC was greater in Irx5−/− mice compared to control. Our results demonstrate that Irx5 regulates regional differences in contractility as well as ventricular dilation and cardiac hypertrophy in response to pressure-overload.