PFKFB3 exacerbates myocardial injury by accelerating CXCR4hi neutrophil mobilization after acute myocardial infarction

TL;DR

This study shows that PFKFB3 worsens heart damage after a heart attack by increasing harmful neutrophil activity.

Contribution

The study reveals a novel role of PFKFB3 in accelerating CXCR4hi neutrophil mobilization after AMI.

Findings

PFKFB3 expression in neutrophils is elevated in AMI patients and linked to higher inflammatory markers.

PFKFB3 promotes CXCR4hi neutrophil mobilization through glycolytic reprogramming in mice.

Neutrophil-specific PFKFB3 knockout reduces myocardial injury in AMI models.

Abstract

CXCR4hi neutrophil mobilization is a key cause of myocardial damage after acute myocardial infarction (AMI). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, plays a crucial role in regulating neutrophil function. However, researchers have not clearly determined whether PFKFB3 is involved in AMI-induced CXCR4hi neutrophil mobilization.

First, the circulating CXCR4hi neutrophil percentage and neutrophil Pfkfb3 mRNA expression were measured in AMI patients and left anterior descending coronary artery (LADCA)-ligated mice. Next, we explored the relationship between PFKFB3 and CXCR4 expression in lipopolysaccharide (LPS)-stimulated cell models. Neu-PFKFB3–/– mice were used to investigate the effect of conditional knockout of the Pfkfb3 gene in neutrophils on AMI-induced myocardial inflammatory injury.

In AMI patients, the expression level of Pfkfb3 gene was markedly regulated in AMI-induced neutrophils and was positively related to the content of plasma inflammatory factors in AMI patients. Further study revealed that PFKFB3 promotes CXCR4hi neutrophil mobilization by reprogramming glycolytic metabolism and subsequently exacerbates inflammatory injury in the myocardial tissues of AMI model mice. However, specific knockout of Pfkfb3 gene in neutrophils protects mice from AMI-induced myocardial inflammatory injury by inhibiting the mobilization of CXCR4hi neutrophils.

PFKFB3 exacerbates AMI-induced myocardial inflammatory injury by accelerating CXCR4hi neutrophil mobilization. The mechanism involves PFKFB3-mediated reprogramming of glycolytic metabolism.

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