GSDMD contributes to myocardial reperfusion injury by regulating pyroptosis

Background: Gasdermin D (GSDMD) plays an essential role in the pathway of pyroptosis. However, whether GSDMD participates in myocardial ischaemia/reperfusion injury (MI/RI) remains poorly understood. Methods: Serum levels of GSDMD and IL-18 in ST-segment elevation myocardial infarction (STEMI) patients were measured by ELISA. The expression of GSDMD and GSDMD N-terminal (GSDMD-NT) in vivo and in vitro was assessed by western blot and immunofluorescence staining. GSDMD(-/-) mice and wild type (WT) mice were induced MI/RI, followed by cardiac ultrasound and histological analysis. Results: Clinically, patients suffering from STEMI after percutaneous coronary intervention (PCI) exhibited higher levels of GSDMD and IL-18 than that in the controls. In vitro, the cleavage of GSDMD was significantly upregulated in macrophages exposed to hypoxia/reoxygenation or H2O2. In vivo, the levels of GSDMD and GSDMD-NT increased notably after MI/RI, especially in macrophages infiltrating in the infarct area. Moreover, compared with WT mice, GSDMD(-/-) mice showed reduced infarct size (25.45 +/- 3.07% versus 36.47 +/- 3.72%), improved left ventricular ejection fraction (37.71 +/- 1.81% versus 29.44 +/- 2.28%) and left ventricular fractional shortening (18.01 +/- 0.97% versus 13.62 +/- 1.15%) as well as attenuated pathological damage after I/R injury, along with reduced levels of proinflammatory cytokines and decreased infiltration of neutrophils. Conclusions: Our study revealed that GSDMD deficiency significantly alleviated the inflammatory response by regulating pyroptosis, reduced the infarct size and preserved cardiac function after MI/RI, thus providing a potential strategy for the treatment of myocardial reperfusion injury.