ROS sensor-effector regulation via cysteine modifications

2012 Fiscal Year Final Research Report

• Project Area: Signaling functions of reactive oxygen species
• Project/Area Number: 20117013
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: NISHIDA Motohiro 九州大学, 薬学研究院, 准教授 (90342641)
• Project Period (FY): 2008 – 2012
• Keywords: 細胞情報伝達学 / 活性酸素 / 心血管

Research Abstract

Reactive oxygen species (ROS), previously established as cause for oxygen toxicity, have been revealed to work as a major mediator in cellular signaling. Oxidative modification of cysteine thiol in the active site of a target protein is involved in this mechanism. We have an interest in the fact that ROS regulate angiotensin type 1 receptor (AT1R) expression levels, and investigated the underlying mechanisms. Pertussis toxin (PTX), a pharmacological inhibitor of receptor-Gi/o protein coupling via ADP-ribosylation of Gα_<i/o> proteins, increases AT1R expression levels through ROS production. PTX was found to increase AT1R density via Toll-like receptor 4-mediated NADPH oxidase activation and subsequent phosphorylation-dependent NF-κB activation. On the other hand, one of inflammatory ligands, ATP, decreases AT1R density through inducible nitric oxide synthase (iNOS)-mediated suppression of NF-κB activity via covalent modification (S-nitrosylation) of NF-κB. The ATP-induced decrease in AT1R density requires direct interaction between NF-κB and iNOS proteins in the cytosol, suggesting that local interaction of NO-generating enzyme with its sensor/effector protein determines the spatio-temporal regulation of NO signaling. Although NO produced via iNOS in the early phase of heart failure contributes to protection of the heart against physical stress, we found that the iNOS-derived NO reacts with intracellular nucleotides (GTP or cGMP) to form electrophilic 8-nitro-cGMP in the later phase of heart failure. We also found that this 8-nitro-cGMP induces cardiac cellular senescence via electrophilic modification (S-guanylation) of Cys-184 on oncogenic H-Ras, a small GTP-binding protein. More interestingly, we revealed that hydrogen sulfide anion (HS-), but not H2S gas, acts as nucleophile, leading to directly guenching electrohpiles, such as 8-nitro-cGMP, resulting in the suppression of heart failure after myocardial infarction via inhibition of cardiac cellular senescence.

Research Products

• [Journal Article] GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance (2013)
  • Author(s): Nakaya M, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Nishida M, Taniguchi H, Sato Y, Matsumoto M, Tsuda M, Kuroda M, Inoue K, Kurose H
  • Journal Title: Nature Commun Volume: 4 Pages: 1532
  • DOI: DOI:10.1038/ncomms2540
  • Peer Reviewed
• [Journal Article] Induction of cardiac fibrosis by β-blocker in G protein-independent and GRK5/β-arrestin2-dependent signaling pathways (2012)
  • Author(s): Nakaya M, Chikura S, Watari K, Mizuno N, Mochinaga K, Mangmool S, Koyanagi S, Ohdo S, Sato Y, Ide T, Nishida M, Kurose H
  • Journal Title: J. Biol. Chem Volume: 287(42) Pages: 35669-35677
  • Peer Reviewed
• [Journal Article] Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis (2012)
  • Author(s): Kan-o M, Takeya R, Abe T, Kitajima N, Nishida M, Tominaga R, Kurose H and Sumimoto H
  • Journal Title: Biol. Open Volume: 1(9) Pages: 889-896
  • Peer Reviewed
• [Journal Article] Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes (2012)
  • Author(s): Fujino T, Ide T, Yoshida M, Onitsuka K, Tanaka A, Hata Y, Nishida M, Takehara T, Kanemaru T, Kitajima N, Takazaki S, Kurose H, Kang D and Sunagawa K
  • Journal Title: Mitochondrion Volume: 12 Pages: 449-458
  • Peer Reviewed
• [Journal Article] Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration (2012)
  • Author(s): Nishida M, Sawa T, Kitajima N, Ono K, Inoue H, Ihara H, Motohashi H, Yamamoto M, Suematsu M, Kurose H, van der Vliet A, Freeman BA, Shibata T, Uchida K, Kumagai Y and Akaike T
  • Journal Title: Nature Chem. Biol Volume: 8 Pages: 714-724
  • Peer Reviewed
• [Journal Article] Protein kinase A-mediated phosphorylation of TRPC6 channels underlies suppression of angiotensin II-induced vasoconstriction. Arterioscler (2011)
  • Author(s): Nishioka K, Nishida M, Ariyoshi M, Saiki S, Jian Z, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R and Kurose H
  • Journal Title: Thromb. Vasc. Biol Volume: 31 Pages: 2278-2286
  • Peer Reviewed
• [Journal Article] TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts (2011)
  • Author(s): Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H and Nishida M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 409 Pages: 108-113
  • Peer Reviewed
• [Journal Article] Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-κB (2011)
  • Author(s): Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K and Kurose H
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Pages: 6662-6627
  • Peer Reviewed
• [Journal Article] Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity (2011)
  • Author(s): Tomonari M, To H, Nishida M, Mishima T, Sasaki H, and Kurose H
  • Journal Title: J. Pharmacol. Sci Volume: 115 Pages: 336-345
  • Peer Reviewed
• [Journal Article] Dual signaling pathways of arterial constriction by extracellular urine 5'-triphosphate in the rat (2011)
  • Author(s): Sugihara M, Morita H, Matsuda M, Umebayashi H, Kajioka S, Ito S, Nishida M, Inoue R, Futatsuki T, Yamazaki J, Mori Y, Inoue R, Ito Y, Abe K and Hirata M
  • Journal Title: J. Pharmacol. Sci Volume: 115 Pages: 293-308
  • Peer Reviewed
• [Journal Article] Inhibition of TRPC6 channel activity contributes to the anti-hypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart (2010)
  • Author(s): Kinoshita H, Kuwahara K, Nishida M, Jiang Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Li Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K and Nakao K
  • Journal Title: Circ. Res Volume: 106 Pages: 1849-1860
  • Peer Reviewed
• [Journal Article] Pertussis toxin upregulates angiotensin type1 receptors through TLR4-mediated Rac activation (2010)
  • Author(s): Nishida M, Suda R, Tanabe S, Onohara N, Nakaya M, Kanaho Y, Sumimoto H, Sato Y and Kurose H
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 15268-15277
  • Peer Reviewed
• [Journal Article] Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition (2010)
  • Author(s): Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima K, Ide T, Inoue R and Kurose H
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 13244-13253
  • Peer Reviewed
• [Journal Article] Ca^<2+> influx and protein scaffolding via TRPC3 sustain PKC■ and ERK activation in B cells (2010)
  • Author(s): Numaga T, Nishida M, Kiyonaka S, Kato K, Katano M, Mori E, Kurosaki T, Inoue R, Hikida M, Putney JW Jr, and Mori Y
  • Journal Title: J. Cell Sci. Volume: 123 Pages: 927-938
  • Peer Reviewed
• [Journal Article] Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound (2009)
  • Author(s): Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y, Yoshida T, Wakamori M, Mori E, Numata T, Ishii M, Takemoto H, Ojida A, Watanabe K, Uemura A, Kurose H, Morii T, Kobayashi T, Sato Y, Sato C, Hamachi I and Mori Y
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 106 Pages: 5400-5405
  • Peer Reviewed
• [Journal Article] Amphotericin B-Induced Renal Tubular Cell Injury is Mediated by Na^+ Influx through Ion-Permeable Pores and Subsequent Activation of MAP Kinases and Elevation of Intracellular Ca2+. Antimicrob (2009)
  • Author(s): Yano T, Itoh Y, Kawamura E, Maeda A, Egashira N, Nishida M, Kurose H, Oishi R
  • Journal Title: Agents Chemother Volume: 53 Pages: 1420-1426
  • Peer Reviewed
• [Journal Article] P2Y6 Receptor-Gα_<12/13> Signaling in Cardiomyocytes Triggers Pressure Overload-induced Cardiac Fibrosis (2008)
  • Author(s): Nishida M, Sato Y, Uemura A, Narita Y, Tozaki-Saitoh H, Nakaya M, Ide T, Suzuki K, Inoue K, Nagao T & Kurose H
  • Journal Title: EMBO J Volume: 27 Pages: 3104-3115
  • Peer Reviewed
• [Journal Article] A food-derived synergist of NGF signaling: Identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction (2008)
  • Author(s): Shibata T, Nakahara H, Kita N, Matsubara Y, Han C, Morimitsu Y, Iwamoto N, Kumagai Y, Nishida M, Kurose H, Aoki N, Ojika M, Uchida K
  • Journal Title: J. Neurochem Volume: 107 Pages: 1248-1260
  • Peer Reviewed
• [Journal Article] Keap1 regulates the constitutive expression of GST A1 during differentiation of Caco-2 cells (2008)
  • Author(s): Kusano Y, Horie S, Shibata T, Satsu H, Shimizu M, Hitomi E, Nishida M, Kurose H, Itoh K, Kobayashi A, Yamamoto M, Uchida K
  • Journal Title: Biochemistry Volume: 47 Pages: 6169-77
  • Peer Reviewed
• [Journal Article] Voltage-dependent N-type Ca^<2+> channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice
  • Author(s): Nishida M, Ishikawa T, Saiki S, Sunggip C, Aritomi S, Harada E, Kuwahara K, Hirano K, Mori Y, Kim-Mitsuyama S
  • Journal Title: Biochem Biophys Res Commun Volume: (in press)
  • DOI: DOI:pii: S0006-291X(13)00456-7
  • Peer Reviewed
• [Presentation] Hydrogen sulfide suppresses H-Ras-mediated cardiac senescence after myocardial infarction via electrophile sulfhydration (2012)
  • Author(s): 西田基宏
  • Organizer: 第33回内藤コンファレンス Oxygen Biology, Hypoxia, Oxidative Stress and Diseases
  • Place of Presentation: Sapporo
  • Year and Date: 20120626-29
• [Presentation] Sulfhydration of Electrophiles Underlies Protection against Reactive Oxygen Species-mediated Cardiac Senescence by Hydrogen Sulfide (2011)
  • Author(s): 西田基宏
  • Organizer: New Aspects of Phospholipid Biology and Medicine 2011 (第10回JBSバイオフロンティア国際シンポジウム)
  • Place of Presentation: Fukuoka
  • Year and Date: 20111114-16
• [Presentation] Diacylglycerol-activated TRPC channels as a new therapeutic target of heart failure (2010)
  • Author(s): 西田基宏
  • Organizer: The 9th International Symposium on 'Recent Trends in Pharmaceutical Sciences
  • Place of Presentation: Yeungnam University, Gyeongsan, Korea
  • Year and Date: 2010-02-04
• [Presentation] P2Y6 receptor-Gα_<12/13> signaling triggers pressure overload-induced cardiac fibrosis (2009)
  • Author(s): Nishida M, Sato Y, Uemura A, Tozaki-Saitoh H, Nakaya M, Inoue K & Kurose H
  • Organizer: Fukuoka Purine 2009 (Joint with JSPS Core-to-Core Program A Satellite Symposium for IUPS2009)
  • Place of Presentation: Fukuoka
  • Year and Date: 20090700
• [Presentation] Role of diacylglycerol-activated TRPC channels in the development of heart failure (2009)
  • Author(s): 西田基宏
  • Organizer: The 6th Japan-Korea Conference on Cellular Signaling for Young Scientists
  • Place of Presentation: Huis Ten Bosch, Nagasaki, Japan
  • Year and Date: 2009-11-25
• [Presentation] Purinergic P2Y6 Receptor in Cardiomyocytes Initiates Pressure Overload-induced Cardiac Fibrosis (2009)
  • Author(s): Nishida M, Uemura A, Nakaya M & Kurose H
  • Organizer: 2009' International Symposium for Pharmaceutical Sciences
  • Place of Presentation: Fukuoka
  • Year and Date: 2009-11-05
• [Presentation] Down-regulation of angiotensin receptors by S-nitrosylation of NF-■B (2009)
  • Author(s): Nishida M
  • Organizer: Society for Free Radical Research (SFRR) International. Free Radical School in Japan 2009
  • Place of Presentation: Joetsu Kokusai Ski Resort, Nagano
  • Year and Date: 2009-09-03
• [Presentation] TRPC channels as a new therapeutic target for heart failure (2009)
  • Author(s): Nishida M
  • Organizer: The 36th Congress of the International Union of Physiological Sciences
  • Place of Presentation: IUPS2009, Kyoto
  • Year and Date: 2009-07-29
• [Presentation] Extracellular nucleotides trigger pressure overload-induced cardiac fibrosis through P2Y6R-Gα_<12/13> signaling pathways (2008)
  • Author(s): Nishida M
  • Organizer: KUSCR Japan/Korea Conference on Cellular Signaling 2008
  • Place of Presentation: Fukuoka
  • Year and Date: 20080000
• [Book] Redox regulation of angiotensin receptor signaling in the heart. Angiotensin: New Research (2012)
  • Author(s): Nishida M, Sunggip C, Kitajima N & Kurose H
  • Total Pages: 165-179
  • Publisher: NOVA Publishers (New York), Edited by Harada S and Moi I
• [Book] Heterotrimeric G proteins in heart failure. Heart Failure: Symptoms, Causes and Treatment Options (2010)
  • Author(s): Nishida M, Ohba M, Nakaya M & Kurose H
  • Total Pages: 51-72
  • Publisher: NOVA Publishers (New York), Edited by Wright MS
• [Remarks]
  • URL: http://soyaku.phar.kyushu-u.ac.jp/