Cooperation Between Hypoxia-Inducible Factor 1α and Activating Transcription Factor 4 in Sleep Apnea-Mediated Myocardial Injury.

Chronic intermittent hypoxia (CIH) occurring during sleep apnea amplifies infarct size owing to ischemia-reperfusion. CIH activates hypoxia-inducible factor 1 (HIF-1) and activating transcription factor 4 (ATF4). However, whether HIF-1 and ATF4 interact to promote cardiomyocyte death remains unexplored. For the first time, we observed that in myocardium from apneic patients, CCAAT enhancer-binding protein homologous protein (CHOP) expression is increased and HIF-1α expression is correlated with sleep apnea severity. In mice, single-allele deletion of HIF-1α prevents CIH increase in CHOP expression and infarct size. We uncovered a physical interaction between HIF-1α and ATF4 in CIH that may represent a novel cardiomyocyte death complex.