Aspirin-Triggered Resolvin D1 Inhibits TGF-β1-Induced EndMT through Increasing the Expression of Smad7 and Is Closely Related to Oxidative Stress

Abstract

The endothelial-mesenchymal transition (EndMT) is known to be involved in the transformation of vascular endothelial cells to mesenchymal cells. EndMT has been confirmed that occur in various pathologic conditions. Transforming growth factor β1 (TGF-β1) is a potent stimulator of the vascular endothelial to mesenchymal transition (EMT). Aspirin-triggered resolvin D1 (ATRvD1) has been known to be involved in the resolution of inflammation, but whether it has effects on TGF-β1-induced EndMT is not yet clear. Therefore, we investigated the effects of AT-RvD1 on the EndMT of human umbilical vein vascular endothelial cells line (HUVECs). Treatment with TGF-β1 reduced the expression of Nrf2 and enhanced the level of F-actin, which is associated with paracellular permeability. The expression of endothelial marker VE-cadherin in HUVEC cells was reduced, and the expression of mesenchymal marker vimentin was enhanced. AT-RvD1 restored the expression of Nrf2 and vimentin and enhanced the expression of VE-cadherin. AT-RvD1 did also affect the migration of HUVEC cells. Inhibitory κB kinase 16 (IKK 16), which is known to inhibit the NF-κB pathway, had an ability to increase the expression of Nrf2 and was associated with the inhibition effect of AT-RvD1 on TGF-β1-induced EndMT, but it had no effect on TGF-β1-induced EndMT alone. Smad7, which is a key regulator of TGF-β/Smads signaling by negative feedback loops, was significantly increased with the treatment of AT-RvD1. These results suggest the possibility that AT-RvD1 suppresses the TGF-β1-induced EndMT through increasing the expression of Smad7 and is closely related to oxidative stress.

Role of endothelial‐to‐mesenchymal transition induced by TGF‐β1 in transplant kidney interstitial fibrosis

“…In the present study, we found that the TGF-b/Smad and Akt/mTOR/p70S6K signalling pathways are required for TGF-b1-induced EndMT, whereas p38 MAPK, Erk 1/2 and JNK signals are not essential for this specific transduction process. Our results confirm those of a number of studies which have confirmed that TGF-b1 is associated with the pathogenesis of EndMT [30][31][32]. Both resident kidney cells and infiltrating leukocytes can secrete TGF-b1, and canonical TGF-b signal transduction involves consecutive processes that include binding of TGF-b1 to TGF-b receptor type II (TGF-bRII), which recruits and phosphorylates TGF-b receptor type I (TGF-bRI) and subsequently activates Smad complexes, which consist of phosphorylated Smad 2/3 and the Cosmad (Smad 4).…”

Hypoxia‐induced endothelial–mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells

“…Notably, it is specifically TGFb2 which is upregulated among the TGFb-family members on mRNA level, and which is also detected as mature TGFb2 in the secretome of endothelial cells upon hypoxia. While in context of fibrosis, the most abundant isoform within fibrotic tissue which had been identified as EndMT-inducing stimulus was TGFb1 [29]. Our observation here is in line with several previous publications which identified TGFb2 as most potent EndMT-inducing stimulus (without negating EndMT-inducing potential of TGFb1) [30][31][32].…”

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

“…These results suggested that EOFAZ inhibits TGF-β1-induced KLF4 and NF-κB activation. A previous study reported that NF-κB is one of key regulators during EndMT in endothelial cells; activation or inhibition of the NF-κB signaling pathway resulted in EndMT reversal (28). In addition, it has been reported that NF-κB is essential for both the induction and maintenance of EndMT (29).…”