熱ショック蛋白質誘導剤（ゲラニルゲラニルアセトン）を用いた老人性難聴モデルマウスの難聴進行の抑制
【背景】老人性難聴とは老化に伴う進行的不可逆的な感音難聴であり，聴力の損失は著しくquality of lifeを低下させるが治療法はいまだない．本研究では生体が持つ根幹的なストレス応答である熱ショック応答と誘導される熱ショック蛋白質（Hsp）に着目した．Hspは変性した蛋白質の品質管理や細胞死を抑制することで生存を促進する．この応答は年齢とともに低下し，進行性神経変性疾患での病因の一つと考えられている．Hspは種々の障害から内耳も保護することが知られている．内耳の老化でHspの変化を調べ，さらに様々な臓器でHsp誘導による保護効果を示し，かつ副作用が少ない薬剤であるGeranylgerany...
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| Published in | 山口医学 Vol. 59; no. 4; pp. 153 - 160 |
|---|---|
| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
山口大学医学会
2010
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0513-1731 1880-4462 |
| DOI | 10.2342/ymj.59.153 |
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| Abstract | 【背景】老人性難聴とは老化に伴う進行的不可逆的な感音難聴であり，聴力の損失は著しくquality of lifeを低下させるが治療法はいまだない．本研究では生体が持つ根幹的なストレス応答である熱ショック応答と誘導される熱ショック蛋白質（Hsp）に着目した．Hspは変性した蛋白質の品質管理や細胞死を抑制することで生存を促進する．この応答は年齢とともに低下し，進行性神経変性疾患での病因の一つと考えられている．Hspは種々の障害から内耳も保護することが知られている．内耳の老化でHspの変化を調べ，さらに様々な臓器でHsp誘導による保護効果を示し，かつ副作用が少ない薬剤であるGeranylgeranylacetone（GGA）を用い老人性難聴モデルマウスに対しての保護効果を検討した．【材料と方法】４-40週齢の早期進行性老人性難聴マウスDBA/2Jと聴力正常のCBA/Nを用いた．GGAは，粉末餌に混ぜて４週齢から投与した．Hsp発現はwestern blot assayで評価した．聴覚評価には聴性脳幹反応検査（ABR）を使用した．組織学的評価をH.E.染色，蛍光免疫染色で評価した．さらに有毛細胞数を評価した．【結果】対照マウスの蝸牛ではHsp70，Hsp110高発現が維持されていた．反対にDBA/2Jでは減少を認めた．このDBA/2JにGGAを投与すると有意にHspが誘導された．Hsp70は主な障害部位の有毛細胞に強く発現を認めた．ABRと有毛細胞欠損数で保護効果を示した．【考察とまとめ】発現の違いが見られたHsp70・Hsp110は，加齢で発症する神経変性疾患においてその重要な役割が示唆されているものである．このことは内耳疾患でも同様の病態が存在することが推察された．GGAによって増強されたHspが強力に様々なpathwayを制御したため保護効果を示すことができたと考えられた． |
|---|---|
| AbstractList | 【背景】老人性難聴とは老化に伴う進行的不可逆的な感音難聴であり，聴力の損失は著しくquality of lifeを低下させるが治療法はいまだない．本研究では生体が持つ根幹的なストレス応答である熱ショック応答と誘導される熱ショック蛋白質（Hsp）に着目した．Hspは変性した蛋白質の品質管理や細胞死を抑制することで生存を促進する．この応答は年齢とともに低下し，進行性神経変性疾患での病因の一つと考えられている．Hspは種々の障害から内耳も保護することが知られている．内耳の老化でHspの変化を調べ，さらに様々な臓器でHsp誘導による保護効果を示し，かつ副作用が少ない薬剤であるGeranylgeranylacetone（GGA）を用い老人性難聴モデルマウスに対しての保護効果を検討した．【材料と方法】４-40週齢の早期進行性老人性難聴マウスDBA/2Jと聴力正常のCBA/Nを用いた．GGAは，粉末餌に混ぜて４週齢から投与した．Hsp発現はwestern blot assayで評価した．聴覚評価には聴性脳幹反応検査（ABR）を使用した．組織学的評価をH.E.染色，蛍光免疫染色で評価した．さらに有毛細胞数を評価した．【結果】対照マウスの蝸牛ではHsp70，Hsp110高発現が維持されていた．反対にDBA/2Jでは減少を認めた．このDBA/2JにGGAを投与すると有意にHspが誘導された．Hsp70は主な障害部位の有毛細胞に強く発現を認めた．ABRと有毛細胞欠損数で保護効果を示した．【考察とまとめ】発現の違いが見られたHsp70・Hsp110は，加齢で発症する神経変性疾患においてその重要な役割が示唆されているものである．このことは内耳疾患でも同様の病態が存在することが推察された．GGAによって増強されたHspが強力に様々なpathwayを制御したため保護効果を示すことができたと考えられた． |
| Author | 御厨, 剛史 |
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| References | 17) Hirakawa T, Rokutan K, Niwaka T, Kishi K. Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 1996; 111: 345-357. 26) Aron Y, Vayssier-Taussat M, Bachelet M, Polla BS. Geranylgeranylacetone protects human monocytes from mitochondrial membrane depolarization independently of Hsp70 expression. Cell Mol Life Sci 2001; 58: 1522-1527. 21) Ohlemiller KK, Gagnon PM. Apical-to-basal gradients in age-related cochlear degeneration and their relationship to "primary" loss of cochlear neurons. J Comp Neurol 2004; 479: 103-116. 11) Bruey JM, Ducasse C, Bonniaud P, Ravagnan L, Susin SA. Hsp 27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2000; 2: 645-652. 4) Zheng QY, Johnson KR. Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice. Hear Res 2001; 154: 45-53. 19) Mikuriya T, Sugahara K, Takemoto T, Tanaka K, Takeno K, Shimogori H, Nakai A, Yamashita H. Geranylgeranylacetone, a heat shock protein inducer, prevents acoustic injury in the guinea pig. Brain Res 2005; 1065: 107-114. 20) Katsuno M, Sang C, Adachi H, Minamiyama M, Waza M, Tanaka F, Doyu M, Sobue G. Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci USA 2005; 102: 16801-16806. 12) Pandey P, Saleh A, Nakazawa A, Kumar S, Srinivasula SM. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 2000; 19: 4310-4322. 18) Otaka M, Yamamoto S, Ogasawara K, Takaoka Y, Noguchi S, Miyazaki T, Nakai A, Odashima M, Matsuhashi T, Watanabe S, Itoh H. The induction mechanism of themolecular chaperone HSP70 in the gastric mucosa by geranylgeranylacetone (HSP-induce). Biochem Biophys Res Commun 2007; 353: 399-404. 1) Someya S, Yamasoba T, Weindruch R, Prolla TA, Tanokura M. Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis. Neurobiol Aging 2006; 28: 1613-1622. 9) Morimoto RI. Regulation of heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998; 12: 3788-3796. 16) Sugahara K, Inouye S, Izu H, Katoh Y, Katsuki K, Takemoto T, Shimogori H, Yamashita H, Nakai A. Heat shock transcription factor HSF1 is required for survival of sensory hair cells against acoustic overexposure. Hear Res 2003; 182: 88-96. 15) Akizuki H, Yoshie H, Morita Y, Takahashi K, Hara A. Nuclear transition of heat shock protein in guinea pig cochlea after hyperthermia. Hear Res 1995; 92: 126-130. 14) Fairfield DA, Kanicki AC, Lomax MI, Altschuler RA. Expression and localization of heat shock factor (Hsf) 1 in the rodent cochlea. Hear Res 2002; 173: 109-118. 7) Morley JF, Morimoto RI. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 2004; 15: 657-664. 24) Rokutan K, Teshima S, Kawai T, Kawahara T, Kusumoro K, Mizushima T, Kishi K. Geranylgeranylacetone stimulates mucin synthesis in cultured guinea pig gastric pit cells by inducing a neuronal nitric oxide synthase. J Gastroenterol 2000; 35: 673-681. 5) Siemens J, Lillo C, Dumont RA, Reynolds A, Williams DS, Gillespie PG, Muller U. Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature 2004; 428: 950-955. 6) Fawcett TW, Sylvester SL, Sarge KD, Morimoto RI, Holbrook NJ. Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J Biol Chem 1994; 269: 32272-32278. 13) Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2000; 2: 476-483. 22) Parsell DA, Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Ann Rev Genet 1993; 27: 437-496. 23) Easton DP, Kaneko Y, Subjeck JR. The Hsp110 and Grp1 70 stress proteins: newly recognized relatives of the Hsp70s. Cell Stress Chaperones 2000; 5: 276-290. 25) Hirota K, Nakamura H, Arai T, Ishii H, Bai J, Itoh T, Fukuda K, Yodoi J. Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes. Biochem Biophys Res Commun 2000; 275: 825-830. 3) Johnson KR, Zheng QY, Erway LC. A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice. Genomics 2000; 70: 171-180. 8) Lindquist S. The heat-shock response. Ann Rev Biochem 1986; 55: 1151-1191. 27) Mikuriya T, Sugahara K, Sugimoto K, Fujimoto M, Takemoto T. Attenuation of progressive hearing loss in a model of age-related hearing loss by a heat shock protein inducer, geranylgeranylacetone. Brain Res 2008; 30: 9-17. 10) Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A. Heat shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2000; 2: 469-475. 2) Johnson KR, Erway LC, Cook SA, Willott JF, Zheng QY. A major gene affecting age-related hearing loss in C57BL/6J mice. Hear Res 1997; 114: 83-92. |
| References_xml | – reference: 20) Katsuno M, Sang C, Adachi H, Minamiyama M, Waza M, Tanaka F, Doyu M, Sobue G. Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci USA 2005; 102: 16801-16806. – reference: 6) Fawcett TW, Sylvester SL, Sarge KD, Morimoto RI, Holbrook NJ. Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J Biol Chem 1994; 269: 32272-32278. – reference: 18) Otaka M, Yamamoto S, Ogasawara K, Takaoka Y, Noguchi S, Miyazaki T, Nakai A, Odashima M, Matsuhashi T, Watanabe S, Itoh H. The induction mechanism of themolecular chaperone HSP70 in the gastric mucosa by geranylgeranylacetone (HSP-induce). Biochem Biophys Res Commun 2007; 353: 399-404. – reference: 7) Morley JF, Morimoto RI. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 2004; 15: 657-664. – reference: 3) Johnson KR, Zheng QY, Erway LC. A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice. Genomics 2000; 70: 171-180. – reference: 15) Akizuki H, Yoshie H, Morita Y, Takahashi K, Hara A. Nuclear transition of heat shock protein in guinea pig cochlea after hyperthermia. Hear Res 1995; 92: 126-130. – reference: 1) Someya S, Yamasoba T, Weindruch R, Prolla TA, Tanokura M. Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis. Neurobiol Aging 2006; 28: 1613-1622. – reference: 5) Siemens J, Lillo C, Dumont RA, Reynolds A, Williams DS, Gillespie PG, Muller U. Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature 2004; 428: 950-955. – reference: 16) Sugahara K, Inouye S, Izu H, Katoh Y, Katsuki K, Takemoto T, Shimogori H, Yamashita H, Nakai A. Heat shock transcription factor HSF1 is required for survival of sensory hair cells against acoustic overexposure. Hear Res 2003; 182: 88-96. – reference: 17) Hirakawa T, Rokutan K, Niwaka T, Kishi K. Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 1996; 111: 345-357. – reference: 19) Mikuriya T, Sugahara K, Takemoto T, Tanaka K, Takeno K, Shimogori H, Nakai A, Yamashita H. Geranylgeranylacetone, a heat shock protein inducer, prevents acoustic injury in the guinea pig. Brain Res 2005; 1065: 107-114. – reference: 13) Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2000; 2: 476-483. – reference: 12) Pandey P, Saleh A, Nakazawa A, Kumar S, Srinivasula SM. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 2000; 19: 4310-4322. – reference: 24) Rokutan K, Teshima S, Kawai T, Kawahara T, Kusumoro K, Mizushima T, Kishi K. Geranylgeranylacetone stimulates mucin synthesis in cultured guinea pig gastric pit cells by inducing a neuronal nitric oxide synthase. J Gastroenterol 2000; 35: 673-681. – reference: 10) Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A. Heat shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2000; 2: 469-475. – reference: 11) Bruey JM, Ducasse C, Bonniaud P, Ravagnan L, Susin SA. Hsp 27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2000; 2: 645-652. – reference: 8) Lindquist S. The heat-shock response. Ann Rev Biochem 1986; 55: 1151-1191. – reference: 26) Aron Y, Vayssier-Taussat M, Bachelet M, Polla BS. Geranylgeranylacetone protects human monocytes from mitochondrial membrane depolarization independently of Hsp70 expression. Cell Mol Life Sci 2001; 58: 1522-1527. – reference: 22) Parsell DA, Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Ann Rev Genet 1993; 27: 437-496. – reference: 9) Morimoto RI. Regulation of heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998; 12: 3788-3796. – reference: 2) Johnson KR, Erway LC, Cook SA, Willott JF, Zheng QY. A major gene affecting age-related hearing loss in C57BL/6J mice. Hear Res 1997; 114: 83-92. – reference: 14) Fairfield DA, Kanicki AC, Lomax MI, Altschuler RA. Expression and localization of heat shock factor (Hsf) 1 in the rodent cochlea. Hear Res 2002; 173: 109-118. – reference: 25) Hirota K, Nakamura H, Arai T, Ishii H, Bai J, Itoh T, Fukuda K, Yodoi J. Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes. Biochem Biophys Res Commun 2000; 275: 825-830. – reference: 21) Ohlemiller KK, Gagnon PM. Apical-to-basal gradients in age-related cochlear degeneration and their relationship to "primary" loss of cochlear neurons. J Comp Neurol 2004; 479: 103-116. – reference: 27) Mikuriya T, Sugahara K, Sugimoto K, Fujimoto M, Takemoto T. Attenuation of progressive hearing loss in a model of age-related hearing loss by a heat shock protein inducer, geranylgeranylacetone. Brain Res 2008; 30: 9-17. – reference: 23) Easton DP, Kaneko Y, Subjeck JR. The Hsp110 and Grp1 70 stress proteins: newly recognized relatives of the Hsp70s. Cell Stress Chaperones 2000; 5: 276-290. – reference: 4) Zheng QY, Johnson KR. Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice. Hear Res 2001; 154: 45-53. |
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| Snippet | 【背景】老人性難聴とは老化に伴う進行的不可逆的な感音難聴であり，聴力の損失は著しくquality of lifeを低下させるが治療法はいまだない．本研究では生体が持つ根幹... |
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| SubjectTerms | 熱ショック応答 熱ショック蛋白質 熱ショック蛋白質誘導剤 老人性難聴 |
| Title | 熱ショック蛋白質誘導剤（ゲラニルゲラニルアセトン）を用いた老人性難聴モデルマウスの難聴進行の抑制 |
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