Eplerenone inhibites atrial autonomic nerve remodeling via the ERK1/2 MAPK pathway in a rabbit model of atrial fibrillation
Abstract Aims:Aldosterone is closely associated with atrial fibrillation, and mineralocorticoid receptor antagonists (MRAs) have been proved to be effective in preventing atrial structural remodeling. Atrial autonomic nerve system (ANS) plays an important role in atrial fibrillation (AF). However, the effects of MRAs on ANS remodeling in AF and the underlying mechanisms are still unknown.Main methods:Twenty-one rabbits were randomized into sham, pacing(P), and pacing + eplerenone(P + E) groups. HL-1 cells were subject to control treatment or rapid pacing with or without eplerenone or U0126 (an inhibitor of ERK1/2). Atrial sympathetic and parasympathetic remodeling was detected by immunohistohistochemical analysis, western blotting and reverse transcription-polymerase chain reaction. Circulating neurohormone levels and atrial electrophysiology were also assessed.Key findings:The ERK1/2 MAPK pathway was significantly activated in AF rabbit/HL-1 cell models, resulting in the upregulation of key downstream proteins; this effect was significantly restored by eplerenone(P<0.05). Eplerenone also prevented the changes in circulating neurohormone levels, reduced the mRNA levels of sympathetic- and parasympathetic-related growth factors, and inhibited the inducibility and duration of AF.Significance:Eplerenone inhibited atrial autonomic nerve remodeling and the occurrence of AF by modulating the ERK1/2 MAPK pathway.