Abstract 18603: Estrogen Plays a Protective Role in Advanced Heart Failure by Regulating Target Genes of miR-129-5p Suppressing Cardiac Fibrosis
Background: Moderate cardiac fibrosis has been reported in advanced heart failure (HF) induced by pressure overload in mice. We have previously shown that short term estrogen(E2) therapy starting after the advanced HF can rescue HF. E2 has been shown to reverse fibrosis through estrogen receptor beta(ERb). Here, we explored whether E2 can suppress cardiac fibrosis by inducing miR-129-5p expression through ERb mediated mechanism and verified its key target genes.
Methods and results: We used transaortic constriction to induce HF in male mice, and once the ejection fraction (EF) reached ∼30%, one group of animals was sacrificed (HF group), and the other group received 17b-estradiol via a subcutaneous pellet implant (0.012mg/pellet, n=16) (E2 group) for 10 days. Sham-operated mice served as CTRL. Serial echocardiography was performed to monitor cardiac structure and function. Short-term E2 treatment rescued pressure overload-induced decompensated HF in mice by restoring the EF from 33.17±1.12% to 53.05±1.29(p <0.001). E2 also decreased both interstitial and prevascular fibrosis in HF. MicroRNA microarray analysis and qPCR validation revealed that miR-129-5p is upregulated ∼2 fold in E2 group compared to HF group. Interestingly, miR-129-5p showed no significant change in E2 versus CTRL suggesting altered miR-129-5p expression in HF was restored to CTRL group by E2 treatment. Treatment of HF with ERb agonist (DPN), but not ER-alpha agonist (PPT), also resulted in the upregulation of miR-129-5p indicating the estrogen mediated induction of miR-129-5p is possibly mediated through ERb. In vitro, angiotensin II treatment significantly downregulated miR-129-5p expression in fibroblasts which was restored by estrogen and DPN but not by ERb antagonist (PHPT) further confirming the role of ERb in regulating miR-129-5p. In vitro, over-expression of miR129-5p in fibroblasts resulted in the significant down-regulation of many potential pro-fibrotic target genes including COL1A, PDGFA, GREM1 and the transcription factor SOX4.
Conclusion: Our data strongly suggests that estrogen treatment during HF induces miR-129-5p likely through ERb. Mechanistically, miR-129-5p represses fibrosis by targeting key component genes associated with cardiac fibrosis.
- © 2012 by American Heart Association, Inc.