Mineralocorticoid Receptor Blocker Prevents Mineralocorticoid Receptor–Mediated Inflammation by Modulating Transcriptional Activity of Mineralocorticoid Receptor–p65–Signal Transducer and Activator of Transcription 3 Complex

Abstract

Background Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor‐κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti‐inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti‐inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. Methods and Results Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory‐related gene expression, and elevated serum interleukin‐6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage‐like cell line RAW264.7 cells demonstrated that esaxerenone‐ and spironolactone‐attenuated lipopolysaccharide‐induced interleukin‐6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65–STAT3 interaction, leading to a subsequent increase in interleukin‐6 promoter activity, which was reversed by esaxerenone. Conclusions Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti‐inflammatory properties exerted by modulating the transcriptional activity of the MR–p65–STAT3 complex. These results suggest that the MR–p65–STAT3 complex can be a novel therapeutic target for treating MI.

Keywords

• esaxerenone
• interleukin‐6
• mineralocorticoid receptor
• myocardial infarction