ATP-sensitive potassium channels couple cell excitability to energy metabolism, thereby providing life-saving protection of stressed cardiomyocytes. The signaling for ATP-sensitive potassium channel expression is still unknown. We tested involvement of biochemical and biophysical parameters and potential transcription factors Forkhead box (FOX) and hypoxia-inducible factor (HIF-1alpha). Right atrial tissues were obtained during surgery from 28 children with heart disease. Expression of K(+)-inward-rectifier subunits Kir6.1/Kir6.2; sulfonyl urea receptors (SURs) SUR1A/B and SUR2A/B; and FOX class O (FOXO) 1, FOXO3, FOXF2, and HIF-1alpha were related to 31 parameters, including personal data, blood chemistry, and echocardiography. Venous hypoxemia (but not other ischemia indicators, such as venous hypercapnia or low glucose) predicts increased Kir6.1 (P<0.003) and Kir6.2 (P<0.03) protein. Kir6.1 associates with SUR2A/B mRNA (P<0.05) and correlates with FOXOs (P<0.002). FOXOs correlate with HIF-1alpha (P<0.01) and HIF-1alpha with venous hypoxemia (P<0.003). Electrophoretic mobility-shift assays suggest causal links among hypoxia, HIF-1alpha, FOXO1, and Kir6.1. To mimic mild ischemia encountered in some patients, cultured rat atrial myocytes were tested in hypoxia, hypercapnia, or low glucose, with normal conditions serving as the control. Mild hypoxia (24-hour) increases expression of HIF-1alpha, FOXO1, and SUR2A/B/Kir6.1 in culture (P<0.01), whereas hypercapnia and low glucose have no or opposite effects. Gene knockdown of HIF-1alpha or FOXO1 by small-interfering RNAs abolishes hypoxia-induced expression of FOXO1 and SUR2A/B/Kir6.1. These results suggest that low tissue oxygen determines increased expression of the atrial SUR2A/B/Kir6.1 gene via activation of HIF-1alpha-FOXO1. Because increased SUR2A/B/Kir6.1 has known survival benefits, this pathway offers novel therapeutic targets for children with heart disease.