AUTHOR=Heck-Swain Ka Lin , Li Jiwen , Ruan Wei , Yuan Xiaoyi , Wang Yanyu , Koeppen Michael , Eltzschig Holger K. 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.970415

DOI=10.3389/fcvm.2022.970415

ISSN=2297-055X

ABSTRACT=<p>The transcription factor hypoxia-inducible factor HIF1A induces cardioprotection from ischemia and reperfusion injury. Here, we investigate tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global Hif1a deletion (<italic>Hif1a<sup>loxP/loxP</sup></italic> UbiquitinCre+) have exaggerated myocardial injury during <italic>in situ</italic> ischemia and reperfusion. Surprisingly, this phenotype was mirrored only in mice with myeloid-specific <italic>Hif1a</italic> deletion <italic>(Hif1a<italic><sup>loxP/loxP</sup></italic></italic> LysM Cre+). In contrast, mice with myocardial specific (<italic>Hif1a<sup>loxP/loxP</sup></italic> Myosin Cre+), or vascular <italic>Hif1a</italic> deletion (<italic>Hif1a<sup>loxP/loxP</sup></italic> VEcadherin Cre+) experienced similar levels of injury as controls. Subsequent studies using adoptive transfer of <italic>Hif1a-</italic>deficient polymorphonuclear neutrophils (PMNs) prior to myocardial injury demonstrated increased reperfusion injury. On the contrary, the adoptive transfer of PMNs treated <italic>ex vivo</italic> with the hypoxia inducible factor (HIF) stabilizer dimethyloxalylglycine (DMOG) was associated with attenuated myocardial injury. Furthermore, DMOG-mediated cardioprotection was abolished in <italic>Hif1a<sup>loxP/loxP</sup></italic> LysM Cre+ mice, but not in <italic>Hif2a<sup>loxP/loxP</sup></italic> 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 cardioprotection during ischemia and reperfusion injury, which is mediated, at least in part, by the induction of the netrin-1 neuronal guidance molecule in neutrophils.</p>