title: HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway.
abstract: Genetic predisposition and senescence of retinal pigment epithelium induced by oxidative stress are major contributors to age-related macular degeneration (AMD). Single-nucleotide polymorphisms in HTRA1 are strongly linked to the onset of AMD. In this study, we examine the role of HtrA1 in premature senescence and cell death induced by oxidative stress. HtrA1 mRNA and protein were up-regulated during premature senescence induced by H2O2 in both mouse embryonic fibroblasts (MEFs) and ARPE-19 cells. Expression of the senescence markers p21(CIP1/WAF1) and p16(INK4a), and SA-β-galactosidase activity, were higher in HtrA1+/- MEFs than in HtrA1-/- MEFs. HtrA1+/+ and HtrA1+/- MEFs were more resistant than HtrA1-/- MEFs to H2O2-induced cell death. Activation of p38 MAPK by oxidative stress was quicker in HtrA1+/- MEFs than in HtrA1-/- MEFs. The effects of excess HtrA1 were examined by transient transfection of cells with HtrA1 expression vectors or by addition of recombinant proteins. Excess wild type HtrA1 accelerated premature senescence of MEFs and ARPE-19 cells, while the protease-inactive HtrA1 S328A did not. HtrA1-induced senescence was abrogated by inhibition of p38 MAPK. We conclude that HtrA1 is induced by oxidative stress and promotes premature cell senescence through p38 MAPK in a protease activity-dependent manner.
authors.affiliation: Division of Gene Function in Animals, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.lastname: Supanji
authors.forename: Mari
authors.initials: M
authors.lastname: Shimomachi
authors.forename: Md Zobaer
authors.initials: MZ
authors.lastname: Hasan
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawaichi
authors.forename: Chio
authors.initials: C
authors.lastname: Oka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016922:Cellular Senescence / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases