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Molecular Medicine

, Volume 21, Issue 1, pp 900–911 | Cite as

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling

  • Giuseppina Nicolini
  • Francesca Forini
  • Claudia Kusmic
  • Letizia Pitto
  • Laura Mariani
  • Giorgio Iervasi
Research Article

Abstract

Activation of transforming growth factor (TGF)-β1 signaling in the ischemia/reperfusion (I/R) injured myocardium leads to dysregulation of miR-29-30-133, favoring the profibrotic process that leads to adverse cardiac remodeling (CR). We have previously shown that timely correction of the postischemic low-T3 syndrome (Low-T3S) exerts antifibrotic effects, but the underlying molecular players are still unknown. Here we hypothesize that a prompt, short-term infusion of T3 in a rat model of post I/R Low-T3S could hamper the early activation of the TGFβ1-dependent profibrotic cascade to confer long-lasting cardioprotection against adverse CR. Twenty-four hours after I/R, rats that developed the Low-T3S were randomly assigned to receive a 48-h infusion of 6 µg/kg/d T3 (I/R-L+T3) or saline (I/R-L) and sacrificed at 3 or 14 d post-I/R. Three days post-I/R, Low-T3S correction favored functional cardiac recovery. This effect was paralleled by a drop in TGFβ1 and increased miR-133a, miR-30c and miR-29c in the infarcted myocardium. Consistently, connective transforming growth factor (CTGF) and matrix metalloproteinase-2 (MMP-2), validated targets of the above miRNAs, were significantly reduced. Fourteen days post-I/R, the I/R-L+T3 rats presented a significant reduction of scar size with a better preservation of cardiac performance and LV chamber geometry. At this time, TGFβ1 and miR-29c levels were in the normal range in both groups, whereas miR-30c-133a, MMP-2 and CTGF remained significantly altered in the I/R group. In conclusion, the antifibrotic effect exerted by T3 in the early phase of postischemic wound healing triggers a persistent cardioprotective response that hampers the progression of heart dysfunction and adverse CR.

Notes

Acknowledgments

This work was funded by the Tuscany Region Research Grant (DGR 1157/2011) “Study of the molecular, biochemical and metabolic mechanisms involved in the cardioprotective effect of T3.” We gratefully acknowledge Cristina Barsanti for helpful discussion and the critical reading of this manuscript and Federica Viglione for histology.

Supplementary material

10020_2015_2101900_MOESM1_ESM.pdf (724 kb)
Supplementary material, approximately 723 KB.

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Authors and Affiliations

  • Giuseppina Nicolini
    • 1
  • Francesca Forini
    • 1
  • Claudia Kusmic
    • 1
  • Letizia Pitto
    • 1
  • Laura Mariani
    • 1
  • Giorgio Iervasi
    • 1
  1. 1.CNR Institute of Clinical PhysiologyPisaItaly

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