Gemigliptin Inhibits Interleukin-1ß-Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway.
Endocrinol Metab (Seoul)
; 35(2): 384-395, 2020 06.
Article
en En
| MEDLINE
| ID: mdl-32615723
ABSTRACT
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-1ß (IL-1ß)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor.METHODS:
We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1ß/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-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 non-smad BMP signaling pathways. Gemigliptin inhibited IL-1ß induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1ß-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-1ß. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1ß-induced EndMT.CONCLUSION:
We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1ß-induced EndMT.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Piperidonas
/
Pirimidinas
/
Proteínas Morfogenéticas Óseas
/
Interleucina-1beta
/
Transición Epitelial-Mesenquimal
/
Células Endoteliales de la Vena Umbilical Humana
/
Mesodermo
Idioma:
En
Revista:
Endocrinol Metab (Seoul)
Año:
2020
Tipo del documento:
Article