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.

T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle

“…5C and F). Moreover, as previously observed (Forini et al 2014, Nicolini et al 2015, T 3 improves cardiac functional recovery (Table 3). However, we did not find a significant difference in capillary density in the two groups, even though a more organized pattern of capillary density was observed after T 3 administration ( Fig.…”

“…Several studies demonstrated the beneficial effects of thyroid hormones on CR and function in myocardial infarction, acting not only on cardiomyocytes and cardiofibroblasts but also on endothelial cells and microvasculature (Iervasi & Nicolini 2013, Forini et al 2014, De Castro et al 2015, Gerdes et al 2015, Nicolini et al 2015. Angiogenesis is essential for the recovery after tissue damage, particularly after cardiac and skeletal muscle ischemia (Tomanek & Schatteman 2000, Kessler et al 2014.…”

“…By this model, that closely mimics human AMI disease, 48-h T 3 administration was able to preserve the global heart function to reduce the infarct size as well as cardiomyocyte apoptosis and to improve the myocyte mitochondrial function (Forini et al 2014). Moreover, T 3 reduced the pro-fibrotic process leading to adverse cardiac remodeling (CR) (Nicolini et al 2015).…”

“…Recently, our group published two studies on experimental model of I/R in the early post-ischemic settings and the T 3 administration started after 24 h from the ischemic event to avoid the risk of the presence of unstable cardiovascular and systemic conditions (Forini et al 2014, Nicolini et al 2015. By this model, that closely mimics human AMI disease, 48-h T 3 administration was able to preserve the global heart function to reduce the infarct size as well as cardiomyocyte apoptosis and to improve the myocyte mitochondrial function (Forini et al 2014).…”

Free Triiodothyronine Level Correlates with Myocardial Injury and Prognosis in Idiopathic Dilated Cardiomyopathy: Evidence from Cardiac MRI and SPECT/PET Imaging

“…Conversely, increased accumulation of collagen can occur with low thyroid function, possibly via regulation of collagen gene expression through TH receptors14. A recent publication revealed anti-fibrotic effects of THs through miRNA signaling15. Nonetheless, the paucity of related human data leaves the question open whether low thyroid function is a beneficial or detrimental response in HF.…”