Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of arrhythmogenic cardiomyopathy disease features in vitro and in a murine model.
Does Bay 11-7082 prevent the development of ACM disease features in preclinical models of arrhythmogenic cardiomyopathy?
Inhibition of nuclear factor-κB signaling prevents the development of arrhythmogenic cardiomyopathy features in preclinical models, highlighting inflammation as a potential therapeutic target.
Background: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. Methods: To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. Results: Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of JUP 2157del2 in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 Dsg2 mut/mu t ) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of Dsg2 mut/mut mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. Conclusions: Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.
Chelko et al. (Thu,) conducted a other in Arrhythmogenic cardiomyopathy. Bay 11-7082 was evaluated on Development of arrhythmogenic cardiomyopathy disease features and inflammatory cytokine production. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of arrhythmogenic cardiomyopathy disease features in vitro and in a murine model.