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Gemigliptin Inhibits Interleukin-1ß-Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway.
Hong, Oak-Kee; Lee, Seong-Su; Yoo, Soon Jib; Lee, Min-Kyung; Kim, Mee-Kyoung; Baek, Ki-Hyun; Song, Ki-Ho; Kwon, Hyuk-Sang.
Afiliación
  • Hong OK; Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • Lee SS; Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea.
  • Yoo SJ; Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea.
  • Lee MK; Division of Endocrinology and Metabolism, Department of Internal Medicine, Myongji Hospital, Hanyang University Medical Center, Goyang, Korea.
  • Kim MK; Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • Baek KH; Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • Song KH; Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • Kwon HS; Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Endocrinol Metab (Seoul) ; 35(2): 384-395, 2020 06.
Article en En | MEDLINE | ID: mdl-32615723
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidonas / Pirimidinas / Proteínas Morfogenéticas Óseas / Interleucina-1beta / Transición Epitelial-Mesenquimal / Células Endoteliales de la Vena Umbilical Humana / Mesodermo Límite: Humans Idioma: En Revista: Endocrinol Metab (Seoul) Año: 2020 Tipo del documento: Article Pais de publicación: Corea del Sur
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidonas / Pirimidinas / Proteínas Morfogenéticas Óseas / Interleucina-1beta / Transición Epitelial-Mesenquimal / Células Endoteliales de la Vena Umbilical Humana / Mesodermo Límite: Humans Idioma: En Revista: Endocrinol Metab (Seoul) Año: 2020 Tipo del documento: Article Pais de publicación: Corea del Sur