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Updated: Aug 11, 2025
Herbal Munziq Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting Inflammation
Published on: January 10, 2025
NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis
Wenjing Sun1,2, Hongquan Lu2, Shihua Cui3
1Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450000, China.
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.
Insights
NEDD4 protein inhibits NLRP3 inflammasome activation and pyroptosis, protecting against myocardial ischemia-reperfusion injury. Targeting NEDD4 may prevent microvascular damage post-MI/R.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Biology
Background:
- Myocardial ischemia-reperfusion (MI/R) injury involves complex inflammatory processes and cell death.
- Macrophage inflammation is critical in MI/R pathophysiology, but its role in vascular endothelium function is unclear.
Discussion:
- NEDD4 negatively regulates NLRP3 inflammasome activation and pyroptosis in macrophages.
- NEDD4 stabilizes NLRP3 via SF3A2 interaction, preventing proteasomal degradation.
- Inhibition of NLRP3 inflammasome activation protects cardiac microvascular endothelial cells (CMECs) from injury.
Key Insights:
- NEDD4 deficiency exacerbates MI/R injury, reducing survival and increasing infarct size.
- NEDD4 plays a protective role in the microvasculature during MI/R.
- The NEDD4-SF3A2-NLRP3 axis is a key regulator of pyroptosis in MI/R.
Outlook:
- NEDD4 represents a potential therapeutic target for microvascular injury following myocardial reperfusion.
- Further research into the NEDD4 pathway could reveal novel strategies for treating MI/R.
- Understanding NEDD4's role in macrophage-endothelial cell interactions is crucial for therapeutic development.
