Hypoxia-inducible factor-2α enhances neutrophil survival to promote cardiac injury following myocardial infarction

Heart failure is a major cause of mortality following myocardial infarction. Neutrophils are among the first immune cells to accumulate in the infarcted region. Although beneficial functions of neutrophils in heart injury are now appreciated, neutrophils are also well known for their ability to exacerbate inflammation and promote tissue damage. Myocardial infarction induces hypoxia, where hypoxia-inducible factors (HIFs) are activated and play critical roles in cellular functions. In this context, the role of <i>Hif2α</i> in neutrophils during myocardial infarction is unknown. Here, we demonstrate that neutrophil <i>Hif2α</i> deletion markedly attenuates myocardial infarct size, improves cardiac function, reduces neutrophil survival and tissue accumulation, and correlates with increased macrophage engulfment rates. Mechanistic studies revealed that <i>Hif2α</i> promotes neutrophil survival through binding to hypoxia response element (HRE) in the promoter region of <i>Birc2</i> to regulate expression of the prosurvival factor, cellular inhibitor of apoptosis protein-1 (cIAP1). Inhibition of cIAP1 in neutrophils using the pharmacological agent, Birinapant resulted in increased cell death, establishing a critical role of cIAP1 downstream of <i>Hif2α</i> in neutrophil survival. Taken together, our data demonstrate a protective effect of <i>Hif2α</i> deletion in neutrophils on cardiac injury outcomes through modulation of neutrophil cell survival.<b>NEW & NOTEWORTHY</b> <i>Hif2α</i> in neutrophils increases infarct size, cardiac dysfunction, and ventricular scar after myocardial infarction. <i>Hif2α</i> in neutrophils supports neutrophil survival via cIAP-1 signaling and delays macrophage engulfment.