Abstract
Endothelial mesenchymal transition (EndMT) plays a critical role in the pathogenesis and progression of interstitial and perivascular fibrosis after acute myocardial infarction (AMI). Pigment epithelium-derived factor (PEDF) is shown to be a new therapeutic target owing to its protective role in cardiovascular disease. In this study, we tested the hypothesis that PEDF is an endogenous inhibitor of EndMT and represented a novel mechanism for its protective effects against overactive cardiac fibrosis after AMI. Masson’s trichrome (MTC) staining and picrosirius red staining revealed decreased interstitial and perivascular fibrosis in rats overexpressing PEDF. The protective effect of PEDF against EndMT was confirmed by co-labeling of cells with the myofibroblast and endothelial cell markers. In the endothelial cells of microvessels in the ischemic myocardium, the inhibitory effect of PEDF against nuclear translocation of β-catenin was observed through confocal microscopic imaging. The correlation between antifibrotic effect of PEDF and inactivation of β-catenin was confirmed by co-transfecting cells with lentivirus carrying PEDF or PEDF RNAi and plasmids harboring β-catenin siRNA(r) or constitutive activation of mutant β-catenin. Taken together, these results establish a novel finding that PEDF could inhibit EndMT related cardiac fibrosis after AMI by a mechanism dependent on disruption of β-catenin activation and translocation.
Highlights
Fibrosis in a healing infarct is part of the reparative process, characterized by the fibroblasts accumulation and redundant deposition of extracellular matrix (ECM), and formation of a fibrous scar maintains the integrity of the chamber
Whether the effect of Pigment epithelium-derived factor (PEDF) on cardiac fibrosis is relative to inhibiting endothelial-to-mesenchymal transition (EndMT) and the mechanisms involved remain to be confirmed
We reported that endogenous PEDF expression is related to cardiac fibrosis, and PEDF inhibited cardiac fibrosis especially reduced the perivascular cardiac fibrosis in an acute myocardial infarction (AMI) rat model
Summary
Fibrosis in a healing infarct is part of the reparative process, characterized by the fibroblasts accumulation and redundant deposition of extracellular matrix (ECM), and formation of a fibrous scar maintains the integrity of the chamber. An interesting study by Ueda S et al has demonstrated that PEDF inhibits cardiac fibrosis and several relevant factors such as type III collagen[7]. They have not determined the underlying mechanism of such effects, and the relationship between the endogenous PEDF expression and cardiac fibrosis remains unknown. Recent studies using lineage tracing technique indicate that up to 30% of the fibroblasts formed in the pathogenesis of cardiac fibrosis are derive from endothelial cells via endothelial-to-mesenchymal transition (EndMT)[10]. We explored whether PEDF could ameliorate EndMT-induced cardiac fibrosis through inhibition of β-catenin-signaling pathway
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