MicroRNA-101a suppresses fibrotic programming in isolated cardiac fibroblasts and in vivo fibrosis following trans-aortic constriction

Yue Zhou, Thiam Chien Shiok, Arthur Mark Richards, Peipei Wang
Journal of Molecular and Cellular Cardiology 2018, 121: 266-276

AIMS: MiR-101a is reported to reduce post-infarction myocardial fibrosis through targeting c-FOS and TGFbr1. However the actions of miR-101a within the TGF-β signaling pathway are largely unknown. We demonstrate the mechanisms underlying mutual inhibition between miR-101a and TGF-β signaling and explore the therapeutic potential of miR-101a in suppressing pressure overload-induced cardiac fibrosis.

METHODS AND RESULTS: The effects of miR-101a on fibroblast proliferation, myofibroblast transdifferentiation, collagen synthesis, apoptosis, and autophagy were assessed in isolated rat cardiac fibroblasts (cFB). MiR-101a effects upon cFB TGF-β signaling were assessed by qPCR, Western blotting, 3'UTR luciferase reporter assay and promoter activity assessments. Rats subjected to transverse aortic constriction (TAC) were treated with PBS or 1 mg/kg of a miR-101a mimic i.v. at 1, 3, and 7-day post-surgery. Left ventricular (LV) function (echocardiography; LV catheterization) and LV fibrosis (picro-sirius red staining, qPCR and WB) were assessed at 2-day and 2 & 10-week post-surgery. MiR-101a inhibited cFB proliferation by inducing cell apoptosis rather than through cell cycle inhibition; and reduced collagen synthesis by downregulation of collagen gene expression and increased autophagy. MiR-101a inhibited TGF-β signaling pathways by directly targeting TGFbr1, reducing Smad3 phosphorylation and inhibiting Tab3 promoter activity. Conversely TGF-β inhibited promoter activity for both miR-101a and b. In vivo endogenous miR-101a expression was downregulated 2-day post-TAC returning to baseline by 14-day. MiR-101a mimic treatment inhibited myocardial TGF-β signaling and collagen gene up-regulation at 2-day post-TAC. MiR-101a reduced fibrosis, improved +dP/dt and lowered end diastolic pressure (EDP) at 2-week post-TAC. Treatment also attenuated adverse LV remodeling and preserved cardiac ejection fraction at 10-week post-TAC.

CONCLUSIONS: MiR-101a and TGF-β are mutually inhibitory and co-direct the activation, proliferation, and collagen synthesis of cFBs. The predominance of TGF-β signaling over reduced miR-101a expression early post-TAC is associated with cardiac fibrosis and dysfunction. Treatment with miR-101a, introduced early after imposition of abnormal pressure loading, inhibits TGF-β signaling, reduces cardiac fibrosis and preserves LV function.

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