miR-21 promotes cardiac fibroblast-to-myofibroblast transformation and myocardial fibrosis by targeting Jagged1

Abstract Myocardial fibrosis after myocardial infarction (MI) is a leading cause of heart diseases. MI activates cardiac fibroblasts (CFs) and promotes CF to myofibroblast transformation (CMT). This study aimed to investigate the role of miR-21 in the regulation of CMT and myocardial fibrosis. Primary rat CFs were isolated from young SD rats and treated with TGF-b1, miR-21 sponge or Jagged1 siRNA. Cell proliferation, invasion and adhesion were detected. MI model was established in male SD rats using LAD ligation method and infected with recombinant adenovirus. The heart function and morphology was evaluated by ultrasonic and histological analysis. We found that TGF-b1 induced the up-regulation of miR-21 and down-regulation of Jagged1 in rat CFs. Luciferase assay showed that miR-21 targeted 30-UTR of Jagged1 in rat CFs. miR-21 sponge inhibited the transformation of rat CFs into myofibroblasts, and abolished the inhibition of Jagged1 mRNA and protein expression by TGF-b1. Furthermore, these effects of miR- 21 sponge on rat CFS were reversed by siRNA mediated knockdown of Jagged1. In vivo, heart dysfunction and myocardial fibrosis in MI model rats were partly improved by miR-21 sponge but were aggravated by Jagged1 knockdown. Taken together, these results suggest that miR-21 promotes cardiac fibroblast-to-myofibroblast transforma- tion and myocardial fibrosis by targeting Jagged1. miR-21 and Jagged1 are potential therapeutic targets for myocardial fibrosis.