Dimethyl Fumarate Reverses β-Adrenoceptor-Mediated Myocardial Fibrosis in Mice by Inhibiting Yes-Associated Protein-Regulated Expression of Intermediate-Conductance Ca2+-Activated K+ Channel in Fibroblasts.

BACKGROUND

Myocardial fibrosis is a pivotal pathological component of the failing heart where the sympatho-β-adrenergic receptor (β-AR) signaling is augmented. Intermediate-conductance Ca2+-activated K+ channel (KCa3.1) is expressed in fibroblasts and mediates fibrosis, but the regulation of KCa3.1 expression by β-AR activation remains unclear. Used for treatment of skin diseases, dimethyl fumarate (DMF) is recently found to suppress transcription cofactor yes-associated protein (YAP). Here, we examined whether DMF ameliorates myocardial fibrosis induced by β-AR activation through inhibiting YAP-mediated KCa3.1 expression in fibroblasts.

METHODS

We used 2 mouse models of established cardiac fibrosis induced by administration of isoproterenol (30 mg/kg per d SC) for 1 week with animals studied 4 weeks afterwards, or transgenic overexpression of β2-AR (β2-TG) exhibiting age-related worsening of cardiac fibrosis. In both models, DMF was administered (50 mg/kg per d IP) for 4 weeks. The mechanism of DMF in regulating KCa3.1 expression was studied in cultured adult mouse cardiac fibroblasts exposed to isoproterenol.

RESULTS

Mice subjected to repeated isoproterenol injections developed myocardial inflammation and fibrosis with irreversible cardiac dysfunction. These phenotypes seen in both models were reversed by DMF treatment in vivo. Mechanistically, in both in vivo models and in cultured fibroblasts, we observed declined YAP phosphorylation and enhanced YAP nuclear localization induced by isoproterenol, changes accompanied by upregulation of KCa3.1 expression at mRNA and protein levels. These changes were largely abolished by DMF treatment.

CONCLUSIONS

DMF reverses the established myocardial fibrosis following β-AR activation by inhibiting YAP nuclear localization and resultant KCa3.1 expression in fibroblasts.