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.
Highlights
Adverse cardiac remodeling (CR) after acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide
The miR-29 family targets a host of mRNAs that encode proteins involved in extracellular matrix (ECM) remodeling, including matrix metalloproteinase-2 (MMP-2) [45]. Both miR-30 and miR-133 condition the protein level of connective tissue growth factor (CTGF), and their decrease after myocardial damage leads to fibrosis and conduction anomalies [10,46]. In agreement with these findings reported by other authors, we found that the T3-dependent miRNA modulation was accompanied by decreased matrix metalloprotease (MMP)-2 and CTGF expression 3 d post-I/R
Our data indicate that a protracted postischemic low-T3 syndrome (Low-T3S) is a permissive condition for the maintenance of high TGFβ1 levels in the infarcted myocardium
Summary
Adverse cardiac remodeling (CR) after acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. It is widely recognized that fibroblast transdifferentiation and proliferation is critically involved in the reparative response after myocardial infarction and is implicated in the pathogenesis of cardiac remodeling [1,2,3]. TGFβ1 potentiates its profibrotic action by repressing a set of antifibrotic cardiac microRNAs such as miR-29, miR-30 and miR-133 [6]. Downregulation of these microRNAs after AMI has been causally linked to adverse CR both in humans and animal models [7,8,9,10]. A new strategy aimed at maintaining these miRNA levels in the postischemic setting should blunt extracellular matrix (ECM) remodeling, limiting the progression through CR and heart failure [11,12]
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