Key result
Early methotrexate-lipid core nanoparticle treatment reduced soleus muscle NLRP1 and NLRC4 protein expression but did not improve cardiac remodeling in infarcted rats.
Why the study?
The presence of inflammasomes in skeletal muscle after MI has not been established, and the effects of early MTX-LDE on cardiac remodeling and skeletal muscle inflammatory markers were unknown.
Does early administration of lipid core nanoparticles-associated methotrexate improve cardiac remodeling and reduce skeletal muscle inflammatory markers in infarcted rats?
Does early administration of lipid core nanoparticles-associated methotrexate improve cardiac remodeling and reduce skeletal muscle inflammatory markers in infarcted rats?
Early administration of methotrexate in lipid core nanoparticles reduced specific skeletal muscle inflammatory markers but did not improve cardiac remodeling in a rat model of myocardial infarction.
Does not improve cardiac remodeling despite lowering NLRP1/NLRC4; leaves open inflammasome targeting in preclinical MI models.
Introduction After myocardial infarction (MI), necrotic cardiomyocytes release substances that sensitize nucleotide binding receptors (NLRs) responsible for forming and activating inflamassomes, multiproteic platforms involved in acute inflammation. Although inflammation is useful after heart injury, its persistence may cause deleterious effects in both cardiac and skeletal muscle. The presence of inflamassomes in skeletal muscles after MI has not been established. Methotrexate (MTX) is a potent immunosuppressive drug. Its association with lipid core nanoparticles (MTX-LDE) has shown beneficial effects on cardiac remodeling in infarcted rats. Purpose To evaluate the effects of early MTX-LDE administration on cardiac remodeling and inflammatory markers of infarcted rat soleus muscle. Methods Male Wistar rats were subjected to MI or sham surgery and separated into Sham (n=11), MI (n=11) and MI-MTX (n=14) groups. MI-MTX was initiated 24 h after MI at 1 mg/kg/week, intraperitoneally, for 10 weeks. Only rats with infarction size > 35% total left ventricle (LV) area were included in the study. Echocardiogram was performed at the end of the study. Soleus protein and gene expression of NLRP1, NLRP3, NLRC4, apoptosis-associated speck-like protein containing a CARD (ASC), pro-caspase-1, caspase-1, pro-interleukin (IL)-1 beta, and IL-1 beta were quantified by Western blotting and qPCR, respectively. Statistical analysis: Student t test, ANOVA, and Bonferroni. Results Infarct size did not differ between groups (MI 43 ± 6.2; MI-MTX 43 ± 5.6 % total LV area; p>0.05). Echocardiographic data are shown in the Table. NLRP1 (Sham 1.00 ± 0.34; MI 0.62 ± 0.31; MI-MTX 0.50 ± 0.05* arbitrary units; *p<0.05 vs Sham) and NLRC4 (Sham 1.00 ± 0.29; MI 0.71 ± 0.36; MI-MTX 0.54 ± 0.09* arbitrary units; *p<0.05 vs Sham) protein expression was lower in MI-MTX than Sham. NLRP3, ASC, pro-caspase-1, caspase-1, pro-IL-1 beta, and IL-1 beta protein and gene expression did not differ between groups. Conclusion Early methotrexate administration in lipid core nanoparticles reduces soleus NLRP1 and NLRC4 protein expression despite no improvement in cardiac remodeling in infarcted rats.Echocardiographic data
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Santos et al. (2025) studied this question. Early methotrexate-lipid core nanoparticle treatment reduced soleus muscle NLRP1 and NLRC4 protein expression but did not improve cardiac remodeling in infarcted rats.
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