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Mee-Kyoung Kim 1 Article
Clinical Study
Gemigliptin Inhibits Interleukin-1β–Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway
Oak-Kee Hong, Seong-Su Lee, Soon Jib Yoo, Min-Kyung Lee, Mee-Kyoung Kim, Ki-Hyun Baek, Ki-Ho Song, Hyuk-Sang Kwon
Endocrinol Metab. 2020;35(2):384-395.   Published online June 24, 2020
DOI: https://doi.org/10.3803/EnM.2020.35.2.384
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  • 9 Web of Science
  • 9 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1β (IL-1β)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor.
Methods
We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1β/20 μM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins.
Results
Morphological changes showed gemigliptin blocked IL-1β-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1β activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1β induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1β-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1β. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1β-induced EndMT.
Conclusion
We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1β-induced EndMT.

Citations

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