Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1

The transcription factor hypoxia-inducible factor HIF1A elicitics cardioprotection from ischemia and reperfusion injury. Here, we investigated tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global deletion of Hif1a ( Hif1a loxP/loxP UbiquitinCre+) have exaggerated myocardial injury during in situ ischemia and reperfusion. Surprisingly, this phenotype was mirrored only in mice with myeloid-specific Hif1a deletion (Hif1a loxP/loxP LysM Cre +) . In contrast, mice with myocardial specific ( Hif1a loxP/loxP Myosin Cre +) , or vascular Hif1a deletion ( Hif1a loxP/loxP VEcadherin Cre+) experienced similar injury levels as controls. Subsequent studies using adoptive transfer of Hif1a- deficient polymorphonuclear neutrophils (PMNs) prior to myocardial injury demonstrated increased reperfusion injury. In contrast, adoptive transfer of PMNS treated ex-vivo with the HIF stabilizer dimethyloxalylglycine (DMOG) was associated with attenuated myocardial injury. Moreover, cardioprotection mediated by DMOG was abolished in Hif1a loxP/loxP LysM Cre+ mice, but not in Hif2a loxP/loxP LysM Cre+ mice. Finally, studies of PMN-dependent HIF1A target genes implicated the neuronal guidance molecule netrin-1 in mediating the cardioprotective effects of myeloid HIF1A. Taken together, the present studies identified a functional role for myeloid-expressed HIF1A in providing cardio-protection during ischemia and reperfusion injury, which - at least in part - is mediated by the induction of neuronal guidance molecule netrin-1 in neutrophils. ### Competing Interest Statement The authors have declared no competing interest.