Abstract Heart failure is associated with a low grade and chronic cardiac inflammation that impairs function, however the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac‐specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis, and ventricular dilation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger sensing pathway required for processing the pro‐inflammatory cytokine interleukin‐1β (IL‐1β), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared to WT. Consistent with inflammasome activation, CNTg animals had increased conversion of pro‐caspase‐1 to cleaved and activated forms as well as markedly increased serum IL‐1β. Blockade of IL‐1β signaling via chronic IL‐1 receptor antagonist (IL‐1‐ra) therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro‐inflammatory cytokine maturation, cardiac inflammation and improved systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro‐inflammatory IL‐1β. Blockade of IL‐1β signaling with the IL‐1‐ra reverses these phenotypes, and offers a possible therapeutic approach in the management of heart failure.
Nathan A. Bracey, Paul L. Beck, Daniel A. Muruve, Simon A. Hirota, Jiqing Guo, Habib Jabagi, James R. Wright, Justin A. MacDonald, James P. Lees‐Miller, Daniel Roach, Lisa M. Semeniuk, Henry J. Duff
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