Hypoxia reduces the function and expression of hERG potassium channels (887.2)

Abstract

Human ether‐a‐go‐go‐related gene (hERG) encodes the pore‐forming subunit of the IKr channel which is important for cardiac repolarization. Loss of function of the hERG channel due to mutations or drugs causes long QT syndrome, a cardiac disorder with high risk of cardiac arrhythmias and sudden death. Obstructive Sleep Apnea (OSA) patients who experience intermittent hypoxia display an increased incidence of cardiac arrhythmias. We recently found that OSA patients display a trend of reduced hERG expression in atrial tissues. In the present study, we demonstrate that hypoxic culture (0.5% O2) of neonatal rat cardiomyocytes for 24 h reduced IKr by 80%. However, the same treatment did not affect the amplitudes of Na+ current, Ca2+ current, the transient outward K+ current (Ito) and the inward rectifier K+ current (IK1). Hypoxic culture (0.5% O2) decreased the abundance of hERG channels expressed in HEK 293 cells along with an enhanced expression of HIF1‐ (Hypoxia‐Inducible Factor) which is known to up‐regulate various proteins including proteolytic enzymes. Chemically inducing HIF1‐ by using cobalt chloride also decreased hERG expression. Protease inhibitors including leupeptin (100µM) completely abolished the hypoxic‐induced reduction in hERG expression. Our data raised the possibility that hypoxia decreases hERG expression by activating certain proteases, which degrade the channel protein. Supported by the Canadian Institutes of Health Research ‐ CIHR Grant Funding Source: supported by: CIHR