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Effect of methotrexate associated with lipid core nanoparticles on inflammassome activation and cardiac remodeling in rats with myocardial infarction

Abstract

Despite advances in the treatment of acute myocardial infarction (AMI), the high morbidity and mortality after AMI suggest that pathophysiological mechanisms remain unknown. Myocyte necrosis triggers inflammation, which is followed by a chronic process of cardiac remodeling. The inflammatory process is initiated when pattern recognition receptors (PRRs) of innate immune and myocardial resident cells recognize substances released by necrotic cells and activate signaling cascades leading to the production of inflammatory mediators and leukocyte recruitment. Although inflammation is useful for cellular debris removal, its persistence may intensify cardiac remodeling. The nucleotide binding oligomerization receptors (NLRs) are important PRRs. Some NLRs, such as the NLRP3, are activated by molecules released by necrotic cells and form the inflammasomes, a multiple protein platform that triggers caspase-1 activation. This enzyme cleaves immature forms of pro-IL-1² and pro-IL-18 in mature forms, which recruit leukocytes inducing inflammatory mediator production. The NLRP3 inflammasome is the most studied in AMI; studies have shown that it modulates inflammation and progression of ventricular dysfunction. Although NLRP1 and NLRC4 inflammasomes are involved in inflammatory diseases, their influence in cardiac remodeling after AMI has not been elucidated. Methotrexate (MTX) is an immunomodulator used in the treatment of autoimmune inflammatory diseases. It is also related to cardiovascular risk decrease. A recent study showed that MTX associated with lipid core nanoparticles (LDE-MTX) reduced the post-AMI inflammatory process and improved cardiac function in rodents. We have not identified studies evaluating the effects of MTX on cardiac inflammasomes. We here hypothesize that the improvement in post-AMI cardiac remodeling induced by MTX is related to attenuation of the inflammatory process involving activation of NLRP3, NLRP1 and NLRC4 inflammasomes. Our purpose is to evaluate the effects of LDE-MTX on inflammasome activation, inflammatory response and cardiac remodeling in post-AMI rats. Specific objectives include cardiac evaluation by echocardiogram; assessment of infarcted area by histology; analyses of NLRP1, NLRC4 and NLRP3 expression by Western blot and immunofluorescence; evaluation of expression of genes involved in the inflammasome signaling pathway through RNA-seq; and quantification of serum and myocardial cytokine concentrations by ELISA. To analyze the acute inflammatory process after AMI, the rats will receive LDE-MTX two hours after AMI induction and will be evaluated three days later, when myocardium presents a high degree of inflammation. The effects of LDE-MTX on late cardiac remodeling will be assessed 120 days after AMI induction. As it is not clear whether early inhibition of the inflammatory process is superior to late inhibition, an additional group of rats will receive LDE-MTX administration initiating 21 days after AMI. Statistical analysis: ANOVA and Tukey. (AU)

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