A novel reciprocal loop between microRNA-21 and TGFβRIII is involved in cardiac fibrosis

Cardiac fibrosis is characterized by aberrant proliferation of cardiac fibroblasts and exaggerated deposition of extracellular matrix (ECM) in the myocardial interstitial, and ultimately impairs cardiac function. It is still controversial whether microRNA-21 (miR-21) participates in the process of cardiac fibrosis. Our previous study confirmed that transforming growth factor beta receptor III (TGFβRIII) is a negative regulator of TGF-β pathway. Here, we aimed to decipher the relationship between miR-21 and TGFβRIII in the pathogenic process of myocardial fibrosis. We found that TGF-β1 and miR-21 were up-regulated, whereas TGFβRIII was down-regulated in the border zone of mouse hearts in response to myocardial infarction. After transfection of miR-21 into cardiac fibroblasts, TGFβRIII expression was markedly reduced and collagen content was increased. And, luciferase results confirmed that TGFβRIII was a target of miR-21. It suggests that up-regulation of miR-21 could increase the collagen content and at least in part through inhibiting TGFβRIII. Conversely, we also confirmed that overexpression of TGFβRIII could inhibit the expression of miR-21 and reduce collagen production in fibroblasts. Further studies showed that overexpression of TGFβRIII could also deactivate TGF-β1 pathway by decreasing the expression of TGF-β1 and phosphorylated-Smad3 (p-Smad3). TGF-β1 has been proven as a positive regulator of miR-21. Taken together, we found a novel reciprocal loop between miR-21 and TGFβRIII in cardiac fibrosis caused by myocardial infarction in mice, and targeting this pathway could be a new strategy for the prevention and treatment of myocardial remodeling.

. In response to stimulus, the reciprocal loop of miR-21/TGFβRIII is activated and up-regulation of miR-21 leads to the down-regulation of TGFβRIII, which relieves the inhibition on TGF-β1. Conversely, the increase expression of TGF-β1 activates TGF-β signaling pathway and further up-regulates the expression of miR-21. Once the loop is activated, it will go round and begin again, and finally induces collagen deposition and other ECM proteins involved in fibrosis.Figure optionsDownload high-quality image (146 K)Download as PowerPoint slideHighlights
► microRNA-21 is involved in cardiac fibrosis.
► TGFβRIII is one of the targets of microRNA-21.
► miR-21 increases the collagen content via post-transcription ally regulating TGFβRIII.
► A novel reciprocal loop between miR-21 and TGFβRIII is involved in cardiac fibrosis.
► miR-21/TGFβRIII reciprocal loop would exacerbate the progress of myocardial fibrosis.