title: Transcript profile of cellular senescence-related genes in Fuchs endothelial corneal dystrophy.
abstract: Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disease. Hypothesizing that cellular senescence may be relevant in FECD pathogenesis, genetically undifferentiated late-onset FECD endothelial samples were analyzed to identify common changes of specific senescence-related transcripts. Total RNA was extracted from 21 FECD endothelial samples retrieved from patients undergoing lamellar keratoplasty due to clinically diagnosed end-stage FECD and from 12 endothelial samples retrieved from normal autopsy eyes. Taqman low density array (TLDA) cards were used to analyze differential expression of 89 cellular senescence-related transcripts. Result validation was performed using individual real-time PCR assays. TLDA-analysis demonstrated differential expression of 31 transcripts (fold-change >1.5; p < 0.05). Thereof, 27 showed significant up-regulation and 4 significant down-regulation. Markedly elevated mRNA-levels of the constitutively active and reactive oxygen species-generating enzyme NOX4 were found in all evaluable FECD samples. In addition, increased expression of CDKN2A and its transcriptional activators ETS1 and ARHGAP18 (SENEX) along with decreased expression of CDKN2A inhibitor ID1 were detected in FECD samples. Consistent over-expression of NOX4 in FECD endothelial samples suggests a role as pathogenic factor and as a potential new treatment target in FECD. Transcriptional up-regulation of the CDKN2A-pathway provides further evidence for increased cellular senescence in FECD endothelium.
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, USA; Department of Ophthalmology, University of Cologne, Cologne, Germany; Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Matthaei
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, USA.
authors.forename: Angela Y
authors.initials: AY
authors.lastname: Zhu
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Kallay
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, USA. Electronic address: aljun@jhmi.edu.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Jun
mesh_terms: D017209:Apoptosis; D016922:Cellular Senescence; D004728:Endothelium, Corneal / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005136:Eye Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species
keywords: CDKN2A; Cellular senescence; Corneal endothelium; Fuchs endothelial corneal dystrophy; NOX4; Oxidative stress; Pathogenesis