title: Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling.
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.
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Nicolini
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Forini
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kusmic
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Pitto
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mariani
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iervasi