title: The redox protein p66(shc) mediates cochlear vascular dysfunction and transient noise-induced hearing loss.
abstract: p66(shc), a member of the ShcA protein family, is essential for cellular response to oxidative stress, and elicits the formation of mitochondrial Reactive Oxygen Species (ROS), thus promoting vasomotor dysfunction and inflammation. Accordingly, mice lacking the p66 isoform display increased resistance to oxidative tissue damage and to cardiovascular disorders. Oxidative stress also contributes to noise-induced hearing loss (NIHL); we found that p66(shc) expression and serine phosphorylation were induced following noise exposure in the rat cochlea, together with markers of oxidative stress, inflammation and ischemia as indicated by the levels of the hypoxic inducible factor (HIF) and the vascular endothelial growth factor (VEGF) in the highly vascularised cochlear lateral region and spiral ganglion. Importantly, p66(shc) knock-out (p66 KO) 126 SvEv adult mice were less vulnerable to acoustic trauma with respect to wild type controls, as shown by preserved auditory function and by remarkably lower levels of oxidative stress and ischemia markers. Of note, decline of auditory function observed in 12 month old WT controls was markedly attenuated in p66KO mice consistent with delayed inner ear senescence. Collectively, we have identified a pivotal role for p66(shc) -induced vascular dysfunction in a common pathogenic cascade shared by noise-induced and age-related hearing loss.
authors.affiliation: Department of Head and Neck Surgery, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: A R
authors.initials: AR
authors.lastname: Fetoni
authors.affiliation: Institute of Human Physiology, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: S L M
authors.initials: SL
authors.lastname: Eramo
authors.affiliation: Department of Head and Neck Surgery, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Paciello
authors.affiliation: Department of Head and Neck Surgery, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rolesi
authors.affiliation: Institute of General Pathology, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Samengo
authors.affiliation: Department of Head and Neck Surgery, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Paludetti
authors.affiliation: Institute of Human Physiology, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Troiani
authors.affiliation: Institute of General Pathology, Università Cattolica School of Medicine, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pani
mesh_terms: D000818:Animals; D003051:Cochlea / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism* / Q000503:physiopathology*; D007249:Inflammation / Q000473:pathology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D017208:Rats, Wistar; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000172:deficiency / Q000378:metabolism*
chemical_list: C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1