Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction

Abstract

Phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation build the armory of neutrophils for the first line of defense against invading pathogens. All these processes are modulated by the microenvironment including tonicity, pH and oxygen levels. Here we investigated the neutrophil infiltration in cardiac tissue autopsy samples of patients with acute myocardial infarction (AMI) and compared these with tissues from patients with sepsis, endocarditis, dermal inflammation, abscesses and diseases with prominent neutrophil infiltration. We observed many neutrophils infiltrating the heart muscle after myocardial infarction. Most of these had viable morphology and only few showed signs of nuclear de-condensation, a hallmark of early NET formation. The abundance of NETs was the lowest in acute myocardial infarction when compared to other examined diseases. Since cardiac oxygen supply is abruptly abrogated in acute myocardial infarction, we hypothesized that the resulting tissue hypoxia increased the longevity of the neutrophils. Indeed, the viable cells showed increased nuclear hypoxia inducible factor-1α (HIF-1α) content, and only neutrophils with low HIF-1α started the process of NET formation (chromatin de-condensation and nuclear swelling). Prolonged neutrophil survival, increased oxidative burst and reduced NETs formation were reproduced under low oxygen tensions and by HIF-1α stabilization in vitro. We conclude that nuclear HIF-1α is associated with prolonged neutrophil survival and enhanced oxidative stress in hypoxic areas of AMI.

Moonlighting chromatin: when DNA escapes nuclear control

“…In human acute myocardial infarction, an ischemic disease, infiltrating neutrophils show high nuclear HIF-1α content and remain primarily viable [ 219 ]. In contrast, neutrophils with low nuclear HIF-1α protein levels form NETs [ 219 ].…”

“…In human acute myocardial infarction, an ischemic disease, infiltrating neutrophils show high nuclear HIF-1α content and remain primarily viable [ 219 ]. In contrast, neutrophils with low nuclear HIF-1α protein levels form NETs [ 219 ]. By staying viable in hypoxic tissue neutrophils remain capable of phagocytosis and clear cell debris as an important step of wound healing [ 220 ].…”

Glutathione peroxidase 3 is a novel clinical diagnostic biomarker and potential therapeutic target for neutrophils in rheumatoid arthritis

“…Here, we hypothesized that under low tissue oxygen tensions in the RA SF, neutrophils initiate oxidative stress, activate HIF-1 signaling, and reprogram the glucose metabolism pathway towards PPP to generate more ROS. This has also been observed in neutrophils infiltrating hypoxic myocardium after acute myocardial infarction [ 32 ]. The systematic screening of glycolysis-related genes in synovial neutrophils of patients with RA provided the theoretical basis for future investigations with specific pathway inhibitors.…”

The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co‐Administration Depends on Neuropilin‐1 and Neutrophil Levels

“…[ 46 ] Hypoxia itself may also play a central role in our findings, where apart from directly influencing NRP1 levels, hypoxia is known to increase neutrophil survival [ 47 ] and results in increased degranulation and secretion of MMP‐9 and elastase. [ 48 ] Taken together, we propose that the hypoxic regions in the tumor may in itself upregulate endothelial and tumor cell NRP1 levels while simultaneously attracting neutrophils. The latter will become more active, through which they promote angiogenesis and in this process, neutrophils may also further upregulate NRP1 expression levels.…”