title: Heat shock protein 70 (HSP70) is critical for the photoreceptor stress response after retinal detachment via modulating anti-apoptotic Akt kinase.
abstract: Photoreceptor apoptosis is a major cause of vision loss in many ocular diseases. Significant progress has been made to elucidate the molecular pathways involved in this process, yet little is known about proteins counteracting these apoptotic pathways. It is established that heat shock proteins (HSPs) function as molecular helper proteins (chaperones) by preventing protein aggregation and facilitating refolding of dysfunctional proteins, critical to the survival of all organisms. Here, we investigated the role of HSP70 on photoreceptor survival after experimental retinal detachment (RD) in mice and rats. We found that HSP70 was up-regulated after RD and associated with phosphorylated Akt, thereby preventing its dephosphorylation and further activation of cell death pathways. Administration of quercetin, which inhibits HSP70 and suppresses Akt phosphorylation significantly increased photoreceptor apoptosis. Similarly, RD-induced photoreceptor apoptosis was augmented in mice carrying hypomorphic mutations of the genes encoding HSP70. On the other hand, administration of geranylgeranylacetone, which induces an increase in HSP70 significantly decreased photoreceptor apoptosis after RD through prolonged activation of Akt pathway. Thus, HSP70 may be a favorable potential target to increase photoreceptor cell survival after RD.
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Kayama
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Aristomenis
authors.initials: A
authors.lastname: Thanos
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morizane
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Murakami
authors.forename: Sofia
authors.initials: S
authors.lastname: Theodoropoulou
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Abe
authors.forename: Demetrios
authors.initials: D
authors.lastname: Vavvas
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D012163:Retinal Detachment / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D011794:Quercetin; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C031049:geranylgeranylacetone