MicroRNA-101a suppresses fibrotic programming in isolated cardiac fibroblasts and in vivo fibrosis following trans-aortic constriction
Autor: | Thiam Chien Shiok, Arthur Mark Richards, Peipei Wang, Yue Zhou |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cardiac fibrosis Receptor Transforming Growth Factor-beta Type I Apoptosis Nerve Tissue Proteins Constriction Pathologic 03 medical and health sciences Fibrosis TGF beta signaling pathway Autophagy medicine Animals Humans Smad3 Protein Fibroblast Molecular Biology Cell Proliferation Chemistry Myocardium Fibroblasts Cellular Reprogramming medicine.disease Rats MicroRNAs 030104 developmental biology medicine.anatomical_structure Cell Transdifferentiation Cancer research Myocardial fibrosis Collagen Signal transduction Carrier Proteins Cardiology and Cardiovascular Medicine Proto-Oncogene Proteins c-fos Myofibroblast Signal Transduction |
Zdroj: | Journal of Molecular and Cellular Cardiology. 121:266-276 |
ISSN: | 0022-2828 |
Popis: | 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. |
Databáze: | OpenAIRE |
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