Gemigliptin Inhibits Interleukin-1β–Induced Endothelial Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway

Abstract

Background: Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pm-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1 beta (IL-1 beta)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor.

Methods: We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1 beta/20 mu M gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markets, bone motphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins.

Results: Morphological changes showed gemigliptin blocked IL-1 beta-induced EndMT. upregulated EC madcers, and downregulated smooth muscle and mesenchymal markers. IL-1 beta activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1 beta induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1 beta-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-1 beta. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1 beta-induced EndMT.

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