MicroRNA‐374b induces endothelial‐to‐mesenchymal transition and early lesion formation through the inhibition of MAPK7 signaling

Abstract

Endothelial–mesenchymal transition occurs during intimal hyperplasia and neointima formation via mechanisms that are incompletely understood. Endothelial MAPK7 signaling is a key mechanosensitive factor that protects against endothelial–mesenchymal transition, but its signaling activity is lost in vessel areas that are undergoing pathological remodeling. At sites of vascular remodeling in mice and pigs, endothelial MAPK7 signaling was lost. The TGFβ‐induced microRNA‐374b targets MAPK7 and its downstream effectors in endothelial cells, and its expression induces endothelial–mesenchymal transition. Gain‐of‐function experiments, where endothelial MAPK7 signaling was restored, precluded endothelial–mesenchymal transition. In human coronary artery disease, disease severity is associated with decreased MAPK7 expression levels and increased miR‐374b expression levels. Endothelial–mesenchymal transition occurs in intimal hyperplasia and early lesion formation and is governed in part by microRNA‐374b‐induced silencing of MAPK7 signaling. Restoration of MAPK7 signaling abrogated these pathological effects in endothelial cells expressing miR‐374b. Thus, our data suggest that the TGFβ‐miR‐374b‐MAPK7 axis plays a key role in the induction of endothelial–mesenchymal transition during intimal hyperplasia and early lesion formation and might pose an interesting target for antiatherosclerosis therapy. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Topography-Mediated Myotube and Endothelial Alignment, Differentiation, and Extracellular Matrix Organization for Skeletal Muscle Engineering

“…Sections were cut 10-µm thick and mounted on glass slides. Deparaffinization and antigen retrieval were done as reported previously [ 27 ] Briefly, two washes in xylene for 15 min, one wash in 100% ethanol for 10 min, 3-min washes in 96% and 70% ethanol, and a final wash in demineralized water were performed. Heat- induced antigen retrieval was done in 0.1-M Tris-HCL (0.05% Tween-20 (Sigma-Aldrich/Merck KGaA, Darmstadt, Germany)) pH 9 at 80 °C overnight.…”

EOFAZ inhibits endothelial‑to‑mesenchymal transition through downregulation of KLF4

“…EndMT contributes to neointimal formation in interpositional vein grafts (14). Similarly, EndMT contributes to intimal hyperplasia and early-lesion formation in atherosclerosis (15). Furthermore, EndMT contributes to progression of PAH, atherosclerosis and wound healing (16).…”

Non-coding RNA in endothelial-to-mesenchymal transition

“…Both miR-374b and miR-449a associate with EndMT in the context of atherosclerosis 82 , 83 . Indeed, miR-449a expression culminates in reduced E-Cadherin expression and an increase in the expression of α-SMA and SMAD3 82 .…”

“…Importantly, antagonizing miR-449a expression inhibits the development of atherosclerosis in diabetic mice 82 . Similarly to miR-449a, the expression of miR-374b is elevated in atheroprone regions in vivo , as well as TGF-β1-treated endothelial cells 83 . Overexpression of miR-374b results in decreased expression of the endothelial markers VE-Cadherin and eNOS whereas the expression of mesenchymal markers TAGLN and Calponin increases 83 .…”

“…Similarly to miR-449a, the expression of miR-374b is elevated in atheroprone regions in vivo , as well as TGF-β1-treated endothelial cells 83 . Overexpression of miR-374b results in decreased expression of the endothelial markers VE-Cadherin and eNOS whereas the expression of mesenchymal markers TAGLN and Calponin increases 83 . Interestingly, combined overexpression of miR-374b and MAPK7 (a known antagonist of EndMT) precludes the EndMT induction by miR-374b 83 .…”