Elucidation of the biological diversity of the nitric oxide synthases system

• Project/Area Number: 16K09519
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: University of the Ryukyus
• Principal Investigator: TSUTSUI MASATO 琉球大学, 医学(系)研究科(研究院), 教授 (70309962)
• Research Collaborator: KANAME TADASHI 国立研究開発法人国立成育医療研究センター, ゲノム医療研究部, 部長 (40264288) ; TANIMOTO AKIHIDE 鹿児島大学大学院, 医歯学総合研究科腫瘍病理学講座分子細胞病理学分野, 教授 (10217151)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 一酸化窒素 / 一酸化窒素合成酵素 / マウス / 心筋梗塞 / 脳梗塞 / 硝酸塩 / 亜硝酸塩 / 性差 / 代謝症候群 / 血管内皮機能不全 / 心血管死 / 多様性

Outline of Final Research Achievements

The purpose of the present study was to examine the biological diversity of the nitric oxide (NO) synthases (NOSs) system in vivo. We performed three research projects. In research #1, we revealed that, in myocardial infarction, testosterone exerted beneficial effects in the presence of NOSs, whereas it showed detrimental effects in the absence of NOSs. In research #2, we found that, in cerebral infarction, testosterone exerts detrimental effects in the presence of NOSs, whereas it exhibited protective effects in the absence of NOSs. In research #3, we demonstrated that not only endogenous NOSs system but also exogenous NO production system (dietary nitrite and nitrate) played a role in disease pathogenesis.

Academic Significance and Societal Importance of the Research Achievements

【研究１の学術的意義】過去に高齢男性におけるテストステロンの心筋梗塞予防作用が検討されたが、予想に反して有害な心血管作用が認められたことが報告された。高齢男性ではNO産生が低下していることから、私達の研究１の結果はこの機序を説明しうると考えられた。
【研究２の学術的意義】研究２の結果から、NOSs阻害療法が男性の脳梗塞に有効である可能性が示唆された。
【研究３の学術的意義】研究３では、食事中の硝酸塩／亜硝酸塩の不足がマウスに代謝症候群、血管不全、心臓突然死を引き起こすことを明らかにした。野菜には硝酸塩が豊富に含有されていることから、野菜の摂取が当該疾患の予防に有効である可能性が示唆された。

Research Products

• [Journal Article] Protective Role of Myelocytic Nitric Oxide Synthases Against Hypoxic Pulmonary Hypertension in Mice. (2018)
  • Author(s): Ogoshi T, Tsutsui M, Kido T, Sakanashi M, Naito K, Oda K, Ishimoto H, Yamada S, Wang KY, Toyohira Y, Izumi H, Masuzaki H, Shimokawa H, Yanagihara N, Yatera K, Mukae H.
  • Journal Title: Am J Respir Crit Care Med. Volume: - Issue: 2 Pages: 232-244
  • DOI: 10.1164/rccm.201709-1783oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 代謝症候群，血管不全，心臓突然死における外因性NO産生系の病因的役割 (2018)
  • Author(s): 喜名美香, 坂梨まゆ子, 久保田陽秋,新崎 章, 筒井正人
  • Journal Title: 血管 Volume: 41 Pages: 9-18
• [Journal Article] 硝酸塩／亜硝酸塩の不足は代謝症候群，血管不全，心臓突然死を引き起こす (2018)
  • Author(s): 喜名美香, 坂梨まゆ子, 新崎 章, 筒井正人
  • Journal Title: 日本薬理学雑誌 Volume: 151 Pages: 148-154
  • NAID: 130006655003
• [Journal Article] NO合成酵素と心不全：基礎と臨床 (2018)
  • Author(s): 筒井正人
  • Journal Title: 心不全（第２版）上 ―最新の基礎・臨床研究の進歩― Volume: 76 Pages: 209-215
• [Journal Article] Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice. (2017)
  • Author(s): Kina-Tanada M, Sakanashi M, Tanimoto A, Kaname T, Matsuzaki T, Noguchi K, Uchida T, Nakasone J, Kozuka C, Ishida M, Kubota H, Taira Y, Totsuka Y, Kina SI, Sunakawa H, Omura J, Satoh K, Shimokawa H, Yanagihara N, Maeda S, Ohya Y, Matsushita M, Masuzaki H, Arasaki A, Tsutsui M.
  • Journal Title: Diabetologia. Volume: 60 Issue: 6 Pages: 1138-1152
  • DOI: 10.1007/s00125-017-4259-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Crucial roles of nitric oxide synthases in β-adrenoceptor mediated bladder relaxation in mice. (2017)
  • Author(s): Satake Y, Satoh K, Nogi M, Omura J, Godo S, Miyata S, Saito H, Tanaka S, Ikumi Y, Yamashita S, Kaiho Y, Tsutsui M, Arai Y, Shimokawa H.
  • Journal Title: Am J Physiol. Volume: 312 Issue: 1 Pages: F33-F42
  • DOI: 10.1152/ajprenal.00137.2016
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Inhibitory effects of pine nodule extract and its component, SJ-2, on acetylcholine-induced catecholamine secretion and synthesis in bovine adrenal medullary cells (2017)
  • Author(s): 2.Li X, Horishita T, Toyohira Y, Shao H, Bai J, Bo H, Song X, Ishikane S, Yoshinaga Y, Satoh N, Tsutsui M, Yanagihara N
  • Journal Title: J Pharmacol Sci Volume: 印刷中 Issue: 4 Pages: 268-275
  • DOI: 10.1016/j.jphs.2017.03.006
  • NAID: 120006937805
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells (2016)
  • Author(s): 4.Yoshimura T, Hamada T, Hijioka H, Souda M, Hatanaka K, Yoshioka T, Yamada S, Tsutsui M, Umekita Y, Nakamura N, Tanimoto A
  • Journal Title: Oncotarget Volume: 7 Issue: 31 Pages: 49065-49074
  • DOI: 10.18632/oncotarget.7529
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Deleterious Effect of All Nitric Oxide Synthases in Cerebral Infarction in Male Mice: Involvements of Sex Difference and Testosterone (2018)
  • Author(s): Tsutsui M, Kubota H, Sakanashi M, Noguchi K, Matsuzaki T, Nakasone J, Shimokawa H, Ohya Y, Sugahara K, Kakinohana M
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Protective Role of Myelocytic Nitric Oxide Synthases in Hypoxic Pulmonary Hypertension in Mice (2018)
  • Author(s): Tsutsui M, Ogoshi T, Kido T, Yamada S, Wang KY, Toyohira Y, Shimokawa H, Yanagihara N, Yatera K, Mukae H
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Long-Term Dietary Nitrite and Nitrate Deficiency Causes Metabolic Syndrome, Endothelial Dysfunction, and Cardiovascular Death in Mice (2018)
  • Author(s): Tsutsui M, Kina-Tanada M, Sakanashi M, Matsuzaki T, Noguchi K, Nakasone J, Shimokawa H, Ohya Y, Arasaki A
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] 食事性NOxの心血管保護作用と骨髄NOSsの肺血管保護作用 (2018)
  • Author(s): 筒井正人
  • Organizer: 第71回日本酸化ストレス学会／第18回日本NO学会合同学術集会
  • Invited
• [Presentation] 食事中の硝酸塩／亜硝酸塩の不足は代謝症候群、血管不全、及び突然死を惹起する (2017)
  • Author(s): 筒井正人
  • Organizer: 先端医療実用化推進事業シンポジウム
  • Place of Presentation: パシフィックホテル沖縄 那覇市
  • Year and Date: 2017-03-10
  • Invited
• [Presentation] Deleterious effect of all nitric oxide synthases in cerebral infarction in male mice: involvements of sex difference and testosterone (2017)
  • Author(s): Tsutsui M, Kubota H, Noguchi K, Matsuzaki T, Sakanashi M, Nakasone J, Shimokawa H, Ohya Y, Sugahara K, Kakinohana M
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] 小動物用CTを用いたマウス内臓肥満の解析：硝酸塩／亜硝酸塩の不足はメタボ、血管不全、突然死を引き起こす (2017)
  • Author(s): 筒井正人
  • Organizer: 第12回in vivoイメージングフォーラム2017
  • Invited
• [Presentation] 硝酸塩／亜硝酸塩の不足は代謝症候群、血管不全、心臓突然死を惹起する (2017)
  • Author(s): 筒井正人、喜名美香、坂梨まゆ子、新崎章
  • Organizer: 第2回黒潮カンファレンス
  • Invited
• [Presentation] Long-Term Dietary Nitrite and Nitrate Deficiency Causes Metabolic Syndrome in Mice (2016)
  • Author(s): Tsutsui M, Kina-Tanada M, Sakanashi M, Ishida M, Uchida T, Kubota H, Matsuzaki T, Noguchi K, Nakasone J, Shimokawa H, Ohya Y, Arasaki A
  • Organizer: American Heart Association, Scientific Sessions 2016
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans, Lousiana, USA
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Pathogenetic Role of the Exogenous NO Production System in Metabolic Syndrome (2016)
  • Author(s): Tsutsui M, Kina-Tanada M, Sakanashi M, Otsuji Y, Shimokawa H, Arasaki A
  • Organizer: The 9th Interbnational Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: Sendai International Center, Sendai, Japan
  • Year and Date: 2016-05-21
  • Int'l Joint Research / Invited
• [Remarks] 琉球大学大学院医学研究科薬理学ホームページ
  • URL: http://w3.u-ryukyu.ac.jp/pharmaco/Pharmacology/youkoso_yao_lihe.html