Myocardial ischemia-reperfusion (MI/R) injury remains a critical challenge in cardiovascular therapeutics, with metabolic-inflammatory signaling axis emerging as a critical mediator of pathological outcomes. Yet, the specific metabolic pathways interplay with inflammation to exacerbate MI/R injury remain poorly defined. Here we verify that NETosis of neutrophils is an initiative and causal factor in driving MI/R injury, specifically, platelet activating factor (PAF) secreted by cardiomyocytes during MI/R, drives neutrophil extracellular traps (NETs) formation and subsequent NETosis. Increased expression of PAF synthesis enzyme PLA2G6 explains excessive production of PAF. PAF-induced NETosis requires gasdermin D (GSDMD) mediated pore-forming to facilitate NETs extrusion. Both inhibiting NETs and PAF synthesis significantly alleviate MI/R injury. We further identify dapagliflozin as a potent NETosis inhibitor that protects mice from MI/R injury in a sodium-glucose co-transporter 2 (SGLT2)-independent manner, which targets neutrophil gelatinase-associated lipocalin-2 (LCN2). Notably, increased serum PAF concentration in acute myocardial infarction patients with percutaneous coronary intervention was positively correlated with NETosis and myocardial injury indexes. Of interest, patients receiving dapagliflozin exhibited attenuated myocardial injury in comparison to those without dapagliflozin. Collectively, our study demonstrates PAF serves as a danger signal in triggering NETosis in early MI/R injury, and manipulating PAF-NETosis signal by dapagliflozin or LCN2 inhibitor might be effective in combating MI/R injury.
Wu et al. (Wed,) studied this question.