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Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this...

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Published in:Experimental gerontology 2007-04, Vol.42 (4), p.327-336
Main Authors: Riva, Catherine, Donadieu, Emilie, Magnan, Jacques, Lavieille, Jean-Pierre
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description Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-α), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67–74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1 α expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1 α
doi_str_mv 10.1016/j.exger.2006.10.014
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The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-α), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67–74], we noticed many alterations in the cochlea. 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The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. 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Histologically, at 4 weeks, intensive HIF-1 α expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. 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dosage</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>ROS</subject><subject>Schwann cells</subject><subject>Schwann Cells - physiology</subject><subject>Spiral ganglion</subject><subject>Spiral Ganglion - physiopathology</subject><subject>Tumor Necrosis Factor-alpha - analysis</subject><subject>Tumor Suppressor Protein p53 - analysis</subject><subject>Up-Regulation - physiology</subject><issn>0531-5565</issn><issn>1873-6815</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNqFkU1r3DAQhkVoSbZpf0Gh6NSbNxp9-OPQQ9g2TSAQaHMXsjz2arGtrSSH5t9Xm13ILT0Jhud9R8xDyGdga2BQXu3W-HfAsOaMlXmyZiDPyArqShRlDeodWTEloFCqVBfkQ4w7lkEu4JxcQAUSmqZZkefrAYuAo0nY0S2a4OaBjj5G6ma6-X4FdHIWqYvUxOite-GSp78eftPeh8kk52dq5o7e3t3QZMKAie6DT-jmSJd97h6W8UjlxrRFar3djmg-kve9GSN-Or2X5PHmx-Pmtrh_-Hm3ub4vrFQyFXUtLAhlRK-ggarvZYmCma4qoS8VCF7LBoRRpeGyMgi1rWSrlOSq7VXbikvy9VibP_VnwZj05KLFcTQz-iXqinHZ1EL9F-RMcd6IJoPiCNqQ7xSw1_vgJhOeNTB9MKN3-sWMPpg5DLOZnPpyql_aCbvXzElFBr4dAczHeHI5Hq3D2WLnAtqkO-_eXPAPN8GfJA</recordid><startdate>20070401</startdate><enddate>20070401</enddate><creator>Riva, Catherine</creator><creator>Donadieu, Emilie</creator><creator>Magnan, Jacques</creator><creator>Lavieille, Jean-Pierre</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20070401</creationdate><title>Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea</title><author>Riva, Catherine ; 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dosage</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>ROS</topic><topic>Schwann cells</topic><topic>Schwann Cells - physiology</topic><topic>Spiral ganglion</topic><topic>Spiral Ganglion - physiopathology</topic><topic>Tumor Necrosis Factor-alpha - analysis</topic><topic>Tumor Suppressor Protein p53 - analysis</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Riva, Catherine</creatorcontrib><creatorcontrib>Donadieu, Emilie</creatorcontrib><creatorcontrib>Magnan, Jacques</creatorcontrib><creatorcontrib>Lavieille, Jean-Pierre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental gerontology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Riva, Catherine</au><au>Donadieu, Emilie</au><au>Magnan, Jacques</au><au>Lavieille, Jean-Pierre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea</atitle><jtitle>Experimental gerontology</jtitle><addtitle>Exp Gerontol</addtitle><date>2007-04-01</date><risdate>2007</risdate><volume>42</volume><issue>4</issue><spage>327</spage><epage>336</epage><pages>327-336</pages><issn>0531-5565</issn><eissn>1873-6815</eissn><abstract>Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-α), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67–74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1 α expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1 α during hypoxia, the tandem “ HIF-ROS ” induced multiple reactions within the cochlea, like a strong inflammatory response with increased expression of TNF- α, and inhibition of neuronal protection mechanisms with repression of IGF-1.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>17141999</pmid><doi>10.1016/j.exger.2006.10.014</doi><tpages>10</tpages></addata></record>
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subjects Action Potentials - physiology
Age-related hearing loss
Aging - metabolism
Animals
Apoptosis
Apoptosis - physiology
Caspase 3 - metabolism
Cochlea
Cochlea - metabolism
Cochlea - pathology
Cochlea - physiopathology
Cochlear Nerve - physiopathology
Coloring Agents - administration & dosage
Hearing Loss - metabolism
Hearing Loss - physiopathology
Hypoxia - metabolism
Hypoxia - physiopathology
Hypoxia-Inducible Factor 1, alpha Subunit - analysis
Hypoxia-inducible-factor
Immunohistochemistry - methods
Injections, Intravenous
Insulin-Like Growth Factor I - analysis
Mice
Nitroimidazoles - administration & dosage
Reactive Oxygen Species - metabolism
ROS
Schwann cells
Schwann Cells - physiology
Spiral ganglion
Spiral Ganglion - physiopathology
Tumor Necrosis Factor-alpha - analysis
Tumor Suppressor Protein p53 - analysis
Up-Regulation - physiology
title Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea
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