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

Activation of transforming growth factor beta 1 (TGFβ1) signaling in the ischemia/reperfusion (I/R) injured myocardium leads to dysregulation of miR-29-30-133, favoring the pro-fibrotic process that leads to adverse cardiac remodeling (CR). We have previously shown that timely correction of the post-ischemic low-T3 state (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 pro-fibrotic 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 48h infusion of 6μg/kg/die T3 (I/R-L+T3) or saline (I/R-L) and sacrificed at 3d or 14d 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, while miR-30c-133a, MMP-2 and CTGF remained significantly altered in the I/R group.In conclusion, the anti-fibrotic effect exerted by T3 in the early phase of post-ischemic wound healing triggers a persistent cardioprotective response that hampers the progression of heart dysfunction and adverse CR.