Jiing-Chyuan Luo1, Yen-Ling Peng2, Tseng-Shing Chen2, Teh-Ia Huo3, Ming-Chih Hou4, Hui-Chun Huang2, Han-Chieh Lin2, Fa-Yauh Lee2. 1. Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: jcluo@vghtpe.gov.tw. 2. Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan. 3. Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, School of Medicine, Taipei, Taiwan. 4. Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Endoscopic Center for Diagnosis and Therapy, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan.
Abstract
BACKGROUND/ PURPOSE: Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. METHODS: Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. RESULTS: The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. CONCLUSION: Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway.
BACKGROUND/ PURPOSE: Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogreldelays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. METHODS: Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. RESULTS: The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. CONCLUSION:Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway.
Authors: Daniela D'Arcangelo; Francesco Facchiano; Giovanni Nassa; Andrea Stancato; Annalisa Antonini; Stefania Rossi; Cinzia Senatore; Martina Cordella; Claudio Tabolacci; Annamaria Salvati; Roberta Tarallo; Alessandro Weisz; Angelo M Facchiano; Antonio Facchiano Journal: Oncotarget Date: 2016-11-22
Authors: Na Kou; Mei Xue; Lin Yang; Ming-Xuan Zang; Hua Qu; Ming-Ming Wang; Yu Miao; Bin Yang; Da-Zhuo Shi Journal: PLoS One Date: 2018-03-27 Impact factor: 3.240