Inhibition of lactate production reduces neutrophil oxidative burst in patients during reperfused acute myocardial infarction (DGK-Forschungsstipendium)

Neutrophils are one of the first immune cells infiltrating the heart during reperfused acute myocardial infarction (repAMI). Besides cardioprotective functions, they also provoke additional tissue damage by releasing reactive oxygen species (ROS) in an oxidative burst. Neutrophil function and ROS generation in particular are controlled metabolically. For neutrophil mobilization from bone marrow and release of neutrophil extracellular traps (NETs), lactate production turned out to be a main regulator. This study aimed to examine the role of lactate production for neutrophil oxidative burst to reduce neutrophil-induced myocardial injury during repAMI.

Human neutrophils were isolated from healthy volunteers and patients during repAMI 24 hours after interventional reperfusion using magnetic activated cell sorting (MACS). Neutrophil lactate production was inhibited by 1-hour incubation with lactate dehydrogenase (LDH) inhibitor sodium oxamate (100 mM). To provoke neutrophil oxidative burst, cells were stimulated with phorbol-12-myristat-13-acetat (PMA) for 30 minutes. Sodium oxamate led to a significant reduction in intracellular lactate level and NAD+/NADH ratio without decreasing cell viability. This reduction in lactate production led to a decrease in pentose phosphate metabolism with reduction of glucose-6-phosphat dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) expression as well as NADPH levels. Due to lower NADPH supply under sodium oxamate treatment, ROS production by NADPH oxidase 2 (NOX2) was reduced, shown by reduction in oxygen consumption rate (OCR) and H2O2 release in healthy volunteers and patients during repAMI.

Inhibition of lactate production reduces neutrophil oxidative burst by decreasing NADPH supply of pentose phosphate metabolism in healthy volunteers and patients during repAMI.