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=13

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=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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) <italic>in vivo</italic> and <italic>in vitro</italic> was assessed by western blot and immunofluorescence staining. GSDMD<sup>-/-</sup> mice and wild type (WT) mice were induced MI/RI, followed by cardiac ultrasound and histological analysis.</p></sec><sec><title>Results</title><p>Clinically, patients suffering from STEMI after percutaneous coronary intervention (PCI) exhibited higher levels of GSDMD and IL-18 than that in the controls. <italic>In vitro</italic>, the cleavage of GSDMD was significantly upregulated in macrophages exposed to hypoxia/reoxygenation or H<sub>2</sub>O<sub>2</sub>. <italic>In vivo</italic>, 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<sup>-/-</sup> 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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec>