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.