Abstract
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis, and we have reported that the anti-EndMT effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is associated with restoring expression of diabetes-suppressed fibroblast growth factor receptor (FGFR), the key anti-EndMT molecule. FGFR1 is the key inhibitor of EndMT via the suppression of the transforming growth factor β (TGFβ) signaling pathway, and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) inhibits integrin β1, a key factor in activating TGFβ signaling and EndMT. Here, we showed that the close proximity between AcSDKP and FGFR1 was essential for the suppression of TGFβ/smad signaling and EndMT associated with MAP4K4 phosphorylation (P-MAP4K4) in endothelial cells. In cultured human dermal microvascular endothelial cells (HMVECs), the anti-EndMT and anti-TGFβ/smad effects of AcSDKP were lost following treatment with a neutralizing FGFR1 antibody (N-FGFR1) or transfection of FRS2 siRNA. The physical interaction between FGFR1 and P-MAP4K4 in HMVECs was confirmed by proximity ligation analysis and an immunoprecipitation assay. AcSDKP induced P-MAP4K4 in HMVECs, which was significantly inhibited by treatment with either N-FGFR1 or FRS2 siRNA. Furthermore, MAP4K4 knockdown using specific siRNAs induced smad3 phosphorylation and EndMT in HMVECs, which was not suppressed by AcSDKP. Streptozotocin-induced diabetic CD-1 mice exhibited suppression of both FGFR1 and P-MAP4K4 expression levels associated with the induction of TGFβ/smad3 signaling and EndMT in their hearts and kidneys; those were restored by AcSDKP treatment. These data demonstrate that the AcSDKP–FGFR1–MAP4K4 axis has an important role in combating EndMT-associated fibrotic disorders.
Highlights
Endothelial-to-mesenchymal transition (EndMT) contributes to the appearance of fibroblasts and has a critical role in organ fibrosis.[1,2] EndMT is involved in various pathological processes, including kidney fibrosis,[3] cardiac fibrosis[4] and cancer.[5]
In the presence of a neutralizing FGFR1 antibody (N-FGFR1), which suppresses FGFR1 activity in endothelial cells, the close proximity between AcSDKP and FGFR1 was markedly diminished in human dermal microvascular endothelial cell (HMVEC), even with AcSDKP incubation (Figure 1a)
We found that AcSDKP inhibited transforming growth factor β (TGFβ)/smad signaling and EndMT in endothelial cells via the FGFR1/
Summary
Endothelial-to-mesenchymal transition (EndMT) contributes to the appearance of fibroblasts and has a critical role in organ fibrosis.[1,2] EndMT is involved in various pathological processes, including kidney fibrosis,[3] cardiac fibrosis[4] and cancer.[5]. MAP4K4 inhibits integrin β1 activity by inducing moesin.[28] integrin β1 induces the epithelial–mesenchymal transition (EMT) and organ fibrosis via the activation of TGFβ/smad signaling.[29,30,31] We have shown that the interaction between dipeptidyl peptidase 4. We hypothesize that the AcSDKP–FGFR1–MAP4K4 axis has a key role in the suppression of TGFβ/smad signaling and EndMT in endothelial cells
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