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NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, c2003-
    • Subject Terms:
      Pyroptosis* ; Myocardial Reperfusion Injury*/drug therapy; Mice ; Animals ; Humans ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Endothelial Cells/metabolism ; HEK293 Cells ; Macrophages/metabolism ; RNA Splicing Factors/metabolism
    • Abstract:
      Objectives: The inflammatory cascade and cell death post-myocardial ischemia reperfusion (MI/R) are very complex. Despite the understanding that macrophage inflammation has a pivotal role in the pathophysiology of MI/R, the contribution of macrophage inflammatory signals in tailoring the function of vascular endothelium remains unknown.
      Materials and Methods: In the present study, we analyzed the effects of NEDD4 on the NLRP3 inflammasome activation-mediated pyroptosis in vitro after an acute pro-inflammatory stimulus and in vivo in a MI/R mouse model. TTC and Evan's blue dye, Thioflavin S, immunohistochemistry staining, and ELISA were performed in wild-type and NEDD4 deficiency mice. THP-1 cells were transfected with si-NEDD4 or si-SF3A2. HEK293T cells were transfected with NEDD4 or SF3A2 overexpression plasmid. ELISA analyzed the inflammatory cytokines in the cell supernatant. The levels of NEDD4, SF3A2, and NLRP3/GSDMD pathway were determined by Western blot. Protein interactions were evaluated by immunoprecipitation. The protein colocalization in cells was monitored using a fluorescence microscope.
      Results: NEDD4 inhibited NLRP3 inflammasome activation and pyroptosis in THP-1 cells treated with lipopolysaccharide (LPS) and nigericin (Nig). Mechanistically, NEDD4 maintained the stability of NLRP3 through direct interaction with the SF3A2, whereas the latter association with NLRP3 indirectly interacted with NEDD4 promoting proteasomal degradation of NLRP3. Deletion of NLRP3 expression further inhibited the caspase cascade to induce pyroptosis. Interestingly, inhibiting NLRP3 inflammasome activation in THP-1 cells could prevent cardiac microvascular endothelial cells (CMECs) injury. In addition, NEDD4 deficiency decreased animal survival and increased myocardial infarct size, no-reflow area, and promoted macrophages infiltration post-MI/R.
      Conclusions: NEDD4 could be a potential therapeutic target in microvascular injury following myocardial reperfusion. Video Abstract.
      (© 2023. The Author(s).)
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    • Contributed Indexing:
      Keywords: Ischemia/reperfusion; NEDD4; NLRP3 inflammasome; Pyroptosis
    • Accession Number:
      0 (Inflammasomes)
      0 (NLR Family, Pyrin Domain-Containing 3 Protein)
      0 (SF3A2 protein, human)
      0 (RNA Splicing Factors)
    • Publication Date:
      Date Created: 20230203 Date Completed: 20230206 Latest Revision: 20230217
    • Publication Date:
      20250114
    • Accession Number:
      PMC9896697
    • Accession Number:
      10.1186/s12964-022-01022-y
    • Accession Number:
      36732831