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  3. GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation

  • Biomedicines. 2023 Sep 20;11(9):2579. doi: 10.3390/biomedicines11092579.
Shiyao Xie 1 2 3,  Enyong Su 1 2 3,  Xiaoyue Song 1 2 3,  Junqiang Xue 1 2 3,  Peng Yu 4,  Baoli Zhang 1 2 3,  Ming Liu 5 6,  Hong Jiang 1 2 3 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai 201203, China.
  • 3 National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Department of Endocrinology and Metabolism, Fudan Institute of Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 5 Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 6 Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
PMID: 37761020 DOI: 10.3390/biomedicines11092579
Abstract

The initiation of atherosclerotic plaque is characterized by endothelial cell inflammation. In light of gasdermin E's (GSDME) role in Pyroptosis and inflammation, this study elucidates its function in atherosclerosis onset. Employing Gsdme- and Apolipoprotein E-deficient (Gsdme-/-/apoE-/-) and apoE-/- mice, an atherosclerosis model was created on a Western diet (WD). In vitro examinations with human umbilical vein endothelial cells (HUVECs) included oxidized low-density lipoprotein (ox-LDL) exposure. To explore the downstream mechanisms linked to GSDME, we utilized an agonist targeting the stimulator of the interferon genes (STING) pathway. The results showed significant GSDME activation in apoE-/- mice arterial tissues, corresponding with atherogenesis. Gsdme-/-/apoE-/- mice displayed fewer plaques and decreased vascular inflammation. Meanwhile, GSDME's presence was confirmed in endothelial cells. GSDME inhibition reduced the endothelial inflammation induced by ox-LDL. GSDME was linked to mitochondrial damage in endothelial cells, leading to an increase in cytoplasmic double-stranded DNA (dsDNA). Notably, STING activation partially offset the effects of GSDME inhibition in both in vivo and in vitro settings. Our findings underscore the pivotal role of GSDME in endothelial cells during atherogenesis and vascular inflammation, highlighting its influence on mitochondrial damage and the STING pathway, suggesting a potential therapeutic target for vascular pathologies.

Keywords

GSDME; STING pathway; atherosclerosis; endothelial cells; mitochondrial damage; vascular inflammation.

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