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Endothelial Gasdermin D Induces Mitochondrial Damage and Activates the STING Pathway in Lipopolysaccharide-Accelerated Atherosclerosis
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DOI：10.1177/15230864251380286.png)
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Abstract
En 中文
Aims: Chronic inflammation is a widely acknowledged contributor to the development of atherosclerosis. Gasdermin D (GSDMD) serves as a key executor of pyroptosis in inflammatory diseases. This study aims to determine the role of endothelial GSDMD in lipopolysaccharide (LPS)-accelerated atherosclerosis and elucidate its underlying molecular mechanisms. Results: GSDMD expression was aberrantly activated in both LPS-accelerated atherosclerotic animal models and oxidized low-density lipoprotein plus LPS-treated endothelial cell models. Compared with the control, endothelial GSDMD deficiency attenuated the atherogenesis progression and vascular endothelial inflammation induced by LPS and protected against the progression of mitochondrial damage, the release of mitochondrial ROS and mitochondrial DNA, and the activation of the stimulator of interferon genes (STING) pathway both in vivo and in vitro. Mechanistically, endothelial GSDMD expression mediates mitochondrial membrane permeabilization and mitochondrial damage-associated molecular patterns release and triggers the STING pathway to aggravate atherosclerotic progression. In addition, the STING pathway activation was proved to partially reverse the effects of endothelial GSDMD deficiency both in vivo and in vitro. Moreover, the signal transducer and activator of transcription 3 was identified as a positive regulator of GSDMD expression. Innovation and Conclusion: Our findings elucidate the mechanism by which endothelial GSDMD exerts its atherogenic effects by increasing mitochondrial damage and upregulating the STING pathway in LPS-accelerated atherosclerosis. GSDMD promises to be a critical therapeutic target for atherosclerotic cardiovascular diseases. Antioxid. Redox Signal. 00, 000–000.
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