AUTHOR=Ye Xiaomiao , Zhang Peng , Zhang Yuting , Luan Jingyun , Xu Caili , Wu Zhengyu , Ju Dianwen , Hu Wei 

TITLE=GSDMD contributes to myocardial reperfusion injury by regulating pyroptosis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.893914

DOI=10.3389/fimmu.2022.893914

ISSN=1664-3224

ABSTRACT=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 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 blotting 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, 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 shorting (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, reducing the infarct size and preserving cardiac function after MI/RI, thus providing a potential strategy for the treatment of myocardial reperfusion injury. 
Keywords: gasdermin D, myocardial reperfusion injury, pyroptosis, interleukin 1β, interleukin 18