Muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, is a crucial mediator of skeletal muscle atrophy and cardiac hypertrophy in response to pressure overload and exercise. The role of MAFbx in the regulation of cardiac remodeling after myocardial infarction (MI) remains unclear. Permanent coronary ligation of the left coronary artery was performed on MAFbx knockout (KO) and wild-type (WT) mice and MAFbx expression in the WT mice was shown to be significantly increased in the left ventricles after MI. The mortality rate due to post-MI cardiac rupture was significantly decreased in MAFbx KO mice compared to that in the WT mice. DNA microarray and mRNA expression analyses revealed that the upregulation of genes involved in inflammatory processes and cell motility of leukocytes and neutrophils, including Mmp9, Il1b, Cxcl2, and Nlrp3, was significantly attenuated in MAFbx KO mice 1 day after MI. MAFbx downregulation inhibited nuclear factor-κB (Nfkb) activation after MI. Flow cytometry results demonstrated that the myocardial infiltration of neutrophils was suppressed in MAFbx KO mice 1 day after MI. Nlrp3 and Il1b protein levels were decreased in MAFbx KO mice compared with those in the WT mice. MAFbx downregulation significantly attenuated Tnfa-induced Cxcl2, Il1b, and Nlrp3 expression in cardiomyocytes. We conclude that MAFbx plays an important role in the mediation of excessive inflammation, including neutrophil infiltration, inflammasome formation, and production of proinflammatory cytokines through the activation of Nfkb, promoting cardiac rupture after MI.
Keywords: Cardiac rupture; Inflammasome; Muscle atrophy F-box; Myocardial infarction; Neutrophils.
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