Objective: Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine interleukin (IL)-1ß is the most potent inducer of EndMT. We investigated inhibition of IL-1ß-induced EndMT by gemigliptin, a DPP-4 inhibitor.

Methods: We exposed human umbilical vein ECs (HUVECs) to 10 ng/mL IL-1ß/20 uM 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-1ß-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1ß activation of HUVECs is initiated by the BMP/Smad and canonical BMP signaling pathways. Gemigliptin inhibited IL-1ß induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor II. Reversal of IL-1ß-mediated inhibition of BMP-induced Smad 1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the canonical BMP pathway, gemigliptin treatment significantly increased the deactivation of ERK, p38, and JNK by IL-1ß. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix and runt-related transcription factor 2 during IL-1ß-induced EndMT.

Conclusions: We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1ß-induced EndMT.

Disclosure

H. Kwon: None. O. Hong: None. Y. Kang: None. H. Kwon: None. S. Yoo: None.

© 2018 by the American Diabetes Association.
2018
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