Endocan Participates in TGF-β/Smad and AKT/ERK Signaling Coordination and lncRNA Modulation in Human Cardiac Fibroblasts
TL;DR
Findings indicate that endocan is required for the coordinated activation of canonical and non-canonical TGF-β signaling during fibroblast transdifferentiation and suggest its potential involvement in the molecular mechanisms underlying cardiac fibrosis.
Abstract
Endocan, a soluble dermatan sulfate proteoglycan, is increasingly recognized as a regulator of key cellular pathways in both physiological and pathological contexts. While TGF-β is a central mediator of fibrotic remodeling, the role of endocan in this process remains elusive. By performing a transcriptomic dataset analysis [GSE116250], we found that endocan expression is upregulated and correlates with fibrotic markers in human failing hearts. We investigated the role of endocan in an in vitro model of cardiac fibroblasts stimulated with TGF-β. Our results identified endocan as a TGF-β-responsive gene in primary human cardiac fibroblasts. Indeed, by inhibiting endocan expression using a specific siRNA, we demonstrated that this proteoglycan is required for the full expression of key fibrosis-related genes (Col1a1, α-SMA, MMP-3, and MMP-9) and modulates the expression of long non-coding RNAs (MALAT1, H19 and HOTAIR), which are essential for the epigenetic control of the fibroblast phenotype. These effects depend on the modulation of both canonical (SMAD3) and non-canonical (AKT and ERK1/2) TGF-β pathways. Taken together, these findings indicate that endocan is required for the coordinated activation of canonical and non-canonical TGF-β signaling during fibroblast transdifferentiation and suggest its potential involvement in the molecular mechanisms underlying cardiac fibrosis.