Gasdermin D-Mediated Pyroptosis Promotes the Development of Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory cardiovascular disease with a high-morbidity and mortality rate. An increasing number of studies have addressed the crucial contribution of gasdermin D (GSDMD)-mediated pyroptosis, which is triggered by the inflammasomes to the development of atherosclerosis. However, the underlying mechanism is still unclear. This study aimed to uncover the detailed role of GSDMD in the development of atherosclerosis. An atherosclerotic model was established in Gsdmd^-/-/Ldlr^-/- mice and Gsdmd^+/+/Ldlr^-/- mice fed with a high-fat diet. The atherosclerotic lesions, the activation of GSDMD, and the expression level of inflammatory cytokines and chemokines were evaluated. Gsdmd deletion ameliorated the atherosclerotic lesion sizes and the infiltration of immune cells and inflammatory cells in the aortas of mice. Additionally, Gsdmd deletion suppressed the pyroptosis of macrophages and endothelial cells induced by the serum of Ldlr^-/- mice fed with a high-fat diet. Furthermore, the formation of neutrophil extracellular traps was also attenuated by knockout of Gsdmd. Bone marrow chimeras confirmed that the genetic deficiency of Gsdmd in both immune cells and intrinsic cells played a role in the promotion of arteriosclerosis. Collectively, our study demonstrated that Gsdmd deletion hindered the pathogenesis of atherosclerosis by inhibiting endothelial cell and macrophage cell death, and the formation of neutrophil extracellular traps.

Keywords: atherosclerosis; endothelial cells; gasdermin D; macrophages; neutrophil extracellular traps; pyroptosis.