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MAGI1 mediates eNOS activation and NO production in endothelial cells in response to fluid shear stress

  • Ghimire, Kedar Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
  • Zaric, Jelena Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
  • Alday-Parejo, Begoña Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
  • Seebach, Jochen Institute of Anatomy and Vascular Biology, Westfälische, Wilhelms-Universität Münster, Germany - Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University of Muenster, Germany
  • Bousquenaud, Mélanie Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
  • Stalin, Jimmy Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
  • Bieler, Grégory Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
  • Schnittler, Hans-Joachim Institute of Anatomy and Vascular Biology, Westfälische, Wilhelms-Universität Münster, Germany - Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University of Muenster, Germany
  • Rüegg, Curzio Pathology, Department of Oncology, Microbiology and Immunology, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Switzerland
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    27.04.2019
Published in:
  • Cells. - 2019, vol. 8, no. 5, p. 388
English Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE- cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1- mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress- induced and PKA/AMPK dependent eNOS activation and NO production
Faculty
Faculté des sciences et de médecine
Department
Médecine 3ème année
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/307947
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