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

Abstract

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.