title: HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor.
abstract: Homocysteine-inducible, endoplasmic reticulum (ER) stress-inducible, ubiquitin-like domain member 1 (HERPUD1), an ER resident protein, is upregulated in response to ER stress and Ca(2+) homeostasis deregulation. HERPUD1 exerts cytoprotective effects in various models, but its role during oxidative insult remains unknown. The aim of this study was to investigate whether HERPUD1 contributes to cytoprotection in response to redox stress and participates in mediating stress-dependent signaling pathways. Our data showed that HERPUD1 protein levels increased in HeLa cells treated for 30 min with H2O2 or angiotensin II and in aortic tissue isolated from mice treated with angiotensin II for 3 weeks. Cell death was higher in HERPUD1 knockdown (sh-HERPUD1) HeLa cells treated with H2O2 in comparison with control (sh-Luc) HeLa cells. This effect was abolished by the intracellular Ca(2+) chelating agent BAPTA-AM or the inositol 1,4,5-trisphosphate receptor (ITPR) antagonist xestospongin B, suggesting that the response to H2O2 was dependent on intracellular Ca(2+) stores and the ITPR. Ca(2+) kinetics showed that sh-HERPUD1 HeLa cells exhibited greater and more sustained cytosolic and mitochondrial Ca(2+) increases than sh-Luc HeLa cells. This higher sensitivity of sh-HERPUD1 HeLa cells to H2O2 was prevented with the mitochondrial permeability transition pore inhibitor cyclosporine A. We concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca(2+) transfer from the ER to mitochondria.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Paredes
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Natalia
authors.initials: N
authors.lastname: Torrealba
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Navarro-Marquez
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Damian
authors.initials: D
authors.lastname: Gatica
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo-Sagua
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: Pennanen
authors.affiliation: ACCDiS, Cardiovascular Diseases Division, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
authors.forename: Clara
authors.initials: C
authors.lastname: Quiroga
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, GA, USA.
authors.forename: Christa
authors.initials: C
authors.lastname: Caesar
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, GA, USA; Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Institut des Neurosciences Paris-Saclay, UMR 9197, 91190 Gif sur Yvette, France.
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: San Martin
authors.affiliation: Centro de Estudios Moleculares de la Célula, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Jaimovich
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, 838049 Santiago, Chile; Centro de Estudios Moleculares de la Célula, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: slavander@uchile.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: C485932:HERPUD1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D002118:Calcium
keywords: Cell death; HERPUD1; IP3 receptor; Oxidative stress