Human -related gene () encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current () potassium channel, which is important for cardiac repolarization. Impairment of hERG function is the primary cause of acquired long QT syndrome, which predisposes individuals to cardiac arrhythmias and sudden death. Patients with hypoxia due to conditions such as cardiac ischemia or obstructive sleep apnea display increased incidence of cardiac arrhythmias and sudden death. We sought to understand the mechanisms that underlie hypoxia-associated cardiac arrhythmias. Using cell biology and electrophysiologic techniques, we found that hypoxic culture of hERG-expressing human embryonic kidney (HEK) cells and neonatal rat cardiomyocytes reduced hERG current/ and mature ERG channel expression with a concomitant increase in calpain expression. Calpain was actively released into the extracellular milieu and degraded cell-surface hERG. In contrast to hERG, the ether-a-go-go (EAG) channel was not reduced by hypoxic culture. By making chimeric channels between hERG and EAG, we identified that hypoxia-induced calpain degraded hERG by targeting its extracellular S5-pore linker. The scorpion toxin BeKm-1, which is known to selectively bind to the S5-pore linker of hERG, prevented hypoxia-induced hERG reduction. Our data provide novel information about hypoxia-mediated hERG dysfunction and may have biological and clinical implications in hypoxia-associated diseases.-Lamothe, S. M., Song, W., Guo, J., Li, W., Yang, T., Baranchuk, A., Graham, C. H., Zhang, S. Hypoxia reduces mature hERG channels through calpain up-regulation.

BackgroundObstructive Sleep Apnea (OSA) results in intermittent hypoxia leading to atrial remodeling, which, among other things, facilitates development of atrial fibrillation. While much data exists on the macrostructural changes in cardiac physiology induced by OSA, there is a lack of studies looking for histologic changes in human atrial tissue induced by OSA which might lead to the observed macrostructural changes.MethodsA case control study was performed. Patients undergoing coronary artery bypass grafting (CABG) were evaluated for OSA and categorized as high-risk or low-risk. The right atrial tissue samples were obtained during CABG and both microscopic histological analysis and Sirius Red staining were performed.Results18 patients undergoing CABG were included; 10 high-risk OSA and 8 low-risk OSA in evenly matched populations. No statistically significant difference between the two groups was observed in amount of myocytolysis (p = 0.181), nuclear hypertrophy (p = 0.671), myocardial inflammation (p = n/a), amyloid deposition (p = n/a), or presence of thrombi (p = n/a), as measured through routine H&E staining. As well, no statistically significant difference in interstitial and epicardial collagen was observed, as measured by Sirius Red staining (for total tissue: p = 0.619: for myocardium: p = 0.776).ConclusionsIn this pilot study there were no observable histological differences in human right atrial tissue from individuals at high- and low-risk for OSA. Further investigation would be required for more definitive results.

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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