The protective effect of NLRP3 inhibitor MCC950 on acute myocardial injury following high-level spinal cord injury in rats
Liao Ye
Huang Shihong
Chen Hui
Wei Liqin
Li Jiaqi
Lin Lijun
Chen Jiaxin
Lin Zhenyu
He Tingting
Zheng Rujie
Huang Qinfeng
Zheng Ying
Abstract：Objective To investigate the protective effect and mechanism of the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inhibitor(MCC950)on acute-phase myocardial injury following high-level spinal cord injury(SCI)in rats.Methods Eighteen Sprague-Dawley(SD)rats were randomly divided into sham-operated,SCI model and MCC950 intervention groups.A modified Allen's method was used to establish the high-level SCI model,and the intervention group received MCC950 preoperatively.Postoperatively,myocardial ultrastructure was evaluated,serum cardiac troponin I(cTnI)and myocardial tissue inflammatory cytokines interleukin-18(IL-18)and interleukin-1β(1L-1β)levels were measured by enzyme-linked immunosorbent assay(ELISA).Reverse transcription-polymerase chain reaction(RT-PCR)and Western blot were used to assess mRNA and protein expression levels of NLRP3,apoptosis-associated speck-like protein(ASC),cysteinyl aspartate specific proteinase-1(Caspase-1),and gasdermin D(GSDMD)in myocardial tissue.Caspase-1 and TUNEL immunofluorescence double staining were employed to measure myocardial cell pyroptosis rates.Results Compared with the sham-operated group,the SCI group exhibited significant pyroptotic changes in myocardial cells,serum cTnI levels(619.6±95.4 vs.1 435.3±98.1,P＜0.05),and IL-18 and IL-1β in myocardial tissue increased significantly(IL-18:131.1±62.5 vs.493.0±85.0,IL-1β:281.7±83.6 vs.936.7±93.2,all P＜0.05).mRNA and protein expression of the NLRP3/ASC/Caspase-1/GSDMD pathway in myocardial tissue were significantly upregulated(mRNA:NLRP3 1.10±0.13 vs.1.91±0.47,ASC 0.97±0.16 vs.2.40±0.34,Caspase-1 0.95±0.17 vs.2.46±0.28,GSDMD 1.03±0.08 vs.1.82±0.12,protein:NLRP3 0.17±0.05 vs.0.85±0.09,ASC 0.26±0.05 vs.0.48±0.08,Caspase-1 0.27±0.07 vs.0.61±0.06,GSDMD 0.20±0.07 vs.0.57±0.12,all P＜0.05),with increases in myocardial pyroptosis rate(5.27±1.05 vs.26.51±2.72,P＜0.05).Compared with the SCI group,above-mentioned indicators significantly improved after MCC950 intervention,cTnI decreased by 18.5％(1 435.3±148.1 vs.1 181.8±132.9),IL-18 and IL-1β in myocardial tissue decreased significantly(IL-18:493.0±146.0 vs.172.1±49.9,IL-1β:936.7±93.2 vs.501.2±63.6,all P＜0.05),and mRNA and protein expression of pyroptosis-related molecules in the NLRP3/ASC/Caspase-1/GSDMD pathway were significantly downregulated(mRNA:NLRP3 1.91±0.47 vs.1.35±0.25,ASC 2.40±0.34 vs.1.51±0.24,Caspase-1 2.46±0.28 vs.1.69±0.16,GSDMD 1.82±0.12 vs.1.33±0.07;protein:NLRP3 0.85±0.09 vs.0.49±0.06,ASC 0.48±0.08 vs.0.33±0.07,Caspase-10.61±0.06 vs.0.41±0.08,GSDMD 0.57±0.12 vs.0.34±0.06,all P＜0.05),with a 44.5％reduction in myocardial pyroptosis rate(26.51±2.72 vs.14.71±1.56,P＜0.05).Conclusions High-level SCI can induce acute myocardial injury,with its mechanism closely related to NLRP3 inflammasome-mediated pyroptosis.MCC950 exerts cardioprotective effects by inhibiting this pathway.
Keywords：High-level spinal cord injuryMyocardial injuryPyroptosisNucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)MCC950(NLRP3 inhibitor)
Publication Date：2025-06-10
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：8( 494-501 )