Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration

Autores
Marazita, Mariela Claudia; Dugour, Andrea Vanesa; Marquioni Ramella, Melisa Daniela; Figueroa, J.M.; Suburo, Angela Maria
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
AbstractOxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-β-galactosidase (SA-β-Gal) staining, and p16INK4a and p21Waf-Cip1 protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking.
Fil: Marazita, Mariela Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina
Fil: Dugour, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Pablo Cassará; Argentina
Fil: Marquioni Ramella, Melisa Daniela. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina
Fil: Figueroa, J.M.. Fundación Pablo Cassará; Argentina
Fil: Suburo, Angela Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina
Materia
Cellular Senescence
Amd
Sasp
Dna Damage
Oxidative Dna Damage
Cigarette Smoke
Retinal Pigment Epithelial Cells
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/40487
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/40487
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular DegenerationMarazita, Mariela ClaudiaDugour, Andrea VanesaMarquioni Ramella, Melisa DanielaFigueroa, J.M.Suburo, Angela MariaCellular SenescenceAmdSaspDna DamageOxidative Dna DamageCigarette SmokeRetinal Pigment Epithelial Cellshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1AbstractOxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-β-galactosidase (SA-β-Gal) staining, and p16INK4a and p21Waf-Cip1 protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking.Fil: Marazita, Mariela Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; ArgentinaFil: Dugour, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Pablo Cassará; ArgentinaFil: Marquioni Ramella, Melisa Daniela. Universidad Austral. Facultad de Ciencias Biomédicas; ArgentinaFil: Figueroa, J.M.. Fundación Pablo Cassará; ArgentinaFil: Suburo, Angela Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; ArgentinaELSEVIER BV2016-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/40487Marazita, Mariela Claudia; Dugour, Andrea Vanesa; Marquioni Ramella, Melisa Daniela; Figueroa, J.M.; Suburo, Angela Maria; Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration; ELSEVIER BV; Redox Biology; 7; 87; 4-2016; 78-872213-2317CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.redox.2015.11.011info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2213231715300136info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:10:40Zoai:ri.conicet.gov.ar:11336/40487instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:10:41.041CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
title Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
spellingShingle Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
Marazita, Mariela Claudia
Cellular Senescence
Amd
Sasp
Dna Damage
Oxidative Dna Damage
Cigarette Smoke
Retinal Pigment Epithelial Cells
title_short Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
title_full Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
title_fullStr Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
title_full_unstemmed Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
title_sort Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration
dc.creator.none.fl_str_mv Marazita, Mariela Claudia
Dugour, Andrea Vanesa
Marquioni Ramella, Melisa Daniela
Figueroa, J.M.
Suburo, Angela Maria
author Marazita, Mariela Claudia
author_facet Marazita, Mariela Claudia
Dugour, Andrea Vanesa
Marquioni Ramella, Melisa Daniela
Figueroa, J.M.
Suburo, Angela Maria
author_role author
author2 Dugour, Andrea Vanesa
Marquioni Ramella, Melisa Daniela
Figueroa, J.M.
Suburo, Angela Maria
author2_role author
author
author
author
dc.subject.none.fl_str_mv Cellular Senescence
Amd
Sasp
Dna Damage
Oxidative Dna Damage
Cigarette Smoke
Retinal Pigment Epithelial Cells
topic Cellular Senescence
Amd
Sasp
Dna Damage
Oxidative Dna Damage
Cigarette Smoke
Retinal Pigment Epithelial Cells
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv AbstractOxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-β-galactosidase (SA-β-Gal) staining, and p16INK4a and p21Waf-Cip1 protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking.
Fil: Marazita, Mariela Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina
Fil: Dugour, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Pablo Cassará; Argentina
Fil: Marquioni Ramella, Melisa Daniela. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina
Fil: Figueroa, J.M.. Fundación Pablo Cassará; Argentina
Fil: Suburo, Angela Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina
description AbstractOxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-β-galactosidase (SA-β-Gal) staining, and p16INK4a and p21Waf-Cip1 protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking.
publishDate 2016
dc.date.none.fl_str_mv 2016-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/40487
Marazita, Mariela Claudia; Dugour, Andrea Vanesa; Marquioni Ramella, Melisa Daniela; Figueroa, J.M.; Suburo, Angela Maria; Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration; ELSEVIER BV; Redox Biology; 7; 87; 4-2016; 78-87
2213-2317
CONICET Digital
CONICET
url http://hdl.handle.net/11336/40487
identifier_str_mv Marazita, Mariela Claudia; Dugour, Andrea Vanesa; Marquioni Ramella, Melisa Daniela; Figueroa, J.M.; Suburo, Angela Maria; Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration; ELSEVIER BV; Redox Biology; 7; 87; 4-2016; 78-87
2213-2317
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.redox.2015.11.011
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2213231715300136
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv ELSEVIER BV
publisher.none.fl_str_mv ELSEVIER BV
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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