Investigation for the new upstream treatment of arrhythmias targetinggap junction remodeling of cardiomyocyte

• Project/Area Number: 19590818
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: OHKUSA Tomoko Yamaguchi University, 大学院・医学系研究科, 講師 (00294629)
• Co-Investigator(Kenkyū-buntansha): 松崎 益徳 山口大学, 大学院・医学系研究科, 教授 (60116754)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 不整脈 / ギャップ結合 / 治療 / コネキシン / レニン・アンジオテンシン・アルドステロン系 / 心不全

Research Abstract

近年、ギャップ結合をはじめとする不整脈発生基盤の多くの因子が解明され、不整脈発生基質に焦点をあてたupstream 治療の重要性が注目されている。本研究はでin vivo(心肥大/心不全モデル動物)およびin vitro(培養心筋細胞)の実験系を用いて、心房筋・心室筋ギャップ結合の質的・量的変化、それを調節するRAA系とその下流因子の解析、同時に電気生理学的特性の変化を解析し、不整脈の発生・維持機構を分子生物学・生化学・生理学的に同時に解明する新しいアプローチを試みる研究を行った。従来、不整脈の発生・維持に関与するメカニズムの研究は、細胞膜上のチャネル特性を検討する電気生理学的アプローチが主であった。本研究結果は、不整脈の発生・維持に関与するメカニズムを、ギャップ結合リモデリングに焦点をあて、RAA 系を中心とした情報伝達系を解析し、ギャップ結合制御を目的とした不整脈の新しい治療薬の開発につながり、upstream治療に大きく貢献すると思わ

Research Products

• [Journal Article] Effects of aldosterone on Cx43 gap junction expression in neonatal rat cultured cardiomyocytes (2009)
  • Author(s): Shinsuke Suzuki
  • Journal Title: Circulalion Journal (In press)
  • Peer Reviewed
• [Journal Article] Altered expression of connexin43contributes to the arrhythomogenicsubstrate during the development of heartfailure in cardiomyopathic hamster (2008)
  • Author(s): Sato T, Ohkusa T, Honjo H, Suzuki S,Yoshida M, Ishiguro YS, Nakagawa H,Yamazaki M, Yano M, Kodama I, Matsuzaki M
  • Journal Title: Am JPhysiol Heart Circ Physiol 294 Pages: 174-1182
• [Journal Article] Altered expression of connexin43 contributes to the arrhythomogenic substrate during the development of heart failure in cardiomyopathic hamster. (2008)
  • Author(s): Takashi Sato, Tomoko Ohkusa
  • Journal Title: Am J Physiol Heart Circ Physiol 294
  • Peer Reviewed
• [Journal Article] Altered expression of connexin43 contributes to the arrhythomogenic substrate during the development of heart failure in cardiomyopathic hamster. (2008)
  • Author(s): Tomoko Ohkusa and Takashi Sato
  • Journal Title: American Journal of Physiology 294
  • Peer Reviewed
• [Journal Article] Effects of aldosterone onCx43 gap junction expressionin neonatal rat cultured cardiomyocytes (2007)
  • Author(s): Suzuki S, Ohkusa T, Sato T, Yoshida M,Yasui K, Miwa K, Lee JK, Yano M, Kodama I,Matsuzaki M
  • Journal Title: Circ J(in press)
• [Journal Article] Beneficial effects of thedual L- and T-type Ca2+ channel blockerefonidipine on cardiomyopathic hamster (2007)
  • Author(s): Suzuki S, Ohkusa T, Ono K, Sato T,Yoshida M, Yano M, Takebayashi S,Matsuzaki M.
  • Journal Title: Circ J 71(12) Pages: 1970-1796
• [Journal Article] Alfdosterone modulates If current throughgene expression in cultured neonatal ratventriculat myocytes (2007)
  • Author(s): Muto T, Ueda N, Opthof T, Ohkusa T,Nagata K, Suzuki S, Tsuji Y, Horiba M, LeeJK, Honjo H, Kamiya K, Kodama I, Yasui K.
  • Journal Title: Am J Physiol Heart Circ Physiol 293
• [Journal Article] Scavenging FreeRadicals by Low-Dose Carvedilol PreventsRedox-Dependent Ca^<2+> Leak ViaStabilization of Ryanodine Receptor inHeart Failure (2007)
  • Author(s): Mochizuki M,Yano M, Oda T, Tateishi H,Kobayashi S, Yamamoto T, Ikeda Y, OhkusaT, Ikemot N, Matsuzaki M.
  • Journal Title: J Am Coll Cardiol 49(16) Pages: 1772-1732
• [Journal Article] Beneficial effects of the dual L- and T-type Ca2+ channel blocker efonidipine on cardiomyopathic hamster. (2007)
  • Author(s): Tomoko Ohkusa and Shinsuke Suzuki
  • Journal Title: Circulation Journal 71 Pages: 1970-1976
  • NAID: 110006452886
  • Peer Reviewed
• [Presentation] Changes of adhesion junctions precede the gap junction remodeling during the development of heart failure (2009)
  • Author(s): Msaaki Yoshida
  • Organizer: The 73rd Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-22
• [Presentation] Changesof Adhesion Junctions Precede the GapJunction Remodeling during theDevelopment of Heart Failure (2009)
  • Author(s): Masaaki Yoshida, Tomoko Ohkusa, TakashiSatoh, Shinsuke Suzuki, Genzou Takemura,Itsuo Kodama, Masunori Matsuzaki
  • Organizer: The 73rdAnnual Scientific Meeting of The JapaneseCirculation Society
  • Place of Presentation: Osaka
  • Year and Date: 2009-03-21
• [Presentation] Abnormally TightDomain-Domain Interaction at MutationSite could be a Primary Cause ofCatecholaminergic PolymorphicVentricular Tachycardia (2009)
  • Author(s): Takeshi Suetomi, Masafumi Yano, MakotoOno, Xiaojuan Xu, Hitoshi Uchinoumi,Hiroki Tateishi, Shinichi Okuda, MasahiroDoi, Shigeki Kobayashi, Takeshi Yamamoto,Yasuhiro Ikeda, Tomoko Ohkusa, MasunoriMatsuzaki
  • Organizer: The 73rd AnnualScientific Meeting of The JapaneseCirculation Society
  • Place of Presentation: Osaka
  • Year and Date: 2009-03-20
• [Presentation] Defective Inter-domain Interaction mayCause Spontaneous Ca^<2+> Release via ReducedAffinity of Calmodulin Binding to RyR2 inFailing Hearts Failing Hearts (2009)
  • Author(s): Makoto Ono, Masafumi Yano, TakeshiSuetomi, Xiaojuan Xu, Hitoshi Uchinoumi,Shinichi Okuda, Masahiro Doi, ShigekiKobayashi, Takeshi Yamamoto, YasuhiroIkeda, Tomoko Ohkusa, Masunori Matsuzaki,
  • Organizer: The 73rd Annual ScientificMeeting of The Japanese CirculationSociety
  • Place of Presentation: Osaka
  • Year and Date: 2009-03-20
• [Presentation] 不整脈発生気質としての細胞間接着構成タンパク異状モデル動物での検討 (2008)
  • Author(s): 吉田雅昭,大草知子,竹村元三,松崎益徳
  • Organizer: 第93回日本循環器学会中国地方会
  • Place of Presentation: 広島
  • Year and Date: 2008-11-29
• [Presentation] Defective Inter-domain Interaction MayCause Spontaneous Ca^<2+> Release Via ReducedAffinity of Calmodulin Binding to RyR2 inFailing Hearts (2008)
  • Author(s): Makoto Ono, Masafumi Yano, TakeshiSuetomi, Xiaojuan Xu, Hitoshi Uchinoumi,Hiroki Tateishi, Shinichi Okuda, ShigekiKobayashi, Takeshi Yamamoto, YasuhiroIkeda, Tomoko Ohkusa, Masunori Matsuzaki
  • Organizer: Scientific Sessions 2008of American Heart Association
  • Place of Presentation: New Orleans
  • Year and Date: 2008-11-08
• [Presentation] Abnormally Tight Domain-DomainInteraction at Mutation Site Could be aPrimary Cause of CatecholaminergicPolymorphic Ventricular Tachycardia : Insight from RyR2 S2246L/+Knock-In MouseModel (2008)
  • Author(s): Takeshi Suetomi, Masafumi Yano,Xiaojuan Xu, Makoto Ono, Hitoshi Uchinoumi,Hiroki Tateishi, Shinichi Okuda, ShigekiKobayashi, Takeshi Yamamoto, YasuhiroIkeda, Tomoko Ohkusa, Masunori Matsuzaki
  • Organizer: Scientific Sessions 2008 ofAmerican Heart Association
  • Place of Presentation: New Orleans
  • Year and Date: 2008-11-08
• [Presentation] Decreased Affinity of CalmodulinBinding to RyR2 May Cause Leaky Channel inCPVT-Associated Mutation : Insight fromRyR^<2R2474s/+> Knock-In Mouse Model (2008)
  • Author(s): Xiaojuan Xu, Masafumi Yano, TakeshiSuetomi, Makoto Ono, Hitoshi Uchinoumi,Hiroki Tateishi, Shinichi Okuda, ShigekiKobayashi, Takeshi Yamamoto, YasuhiroIkeda, Tomoko Ohkusa, Masunori Matsuzaki
  • Organizer: Scientific Sessions 2008 of American Heart Association
  • Place of Presentation: New Orleans
  • Year and Date: 2008-11-08
• [Presentation] Mutation-Linked, DefectiveInter-Domain Interaction within theCardiac Ryanodine Receptor as a CriticalCause of Catecholaminergic PolymorphicVentricular Tachycardia (CPVT) (2008)
  • Author(s): Hitoshi Uchinoumi, Masafumi Yano,Takeshi Suetomi, Xiaojuan Xu, Makoto Ono,Hiroki Tateishi, Shinichi Okuda, ShigekiKobayashi, Takeshi Yamamoto, YasuhiroIkeda, Tomoko Ohkusa, Masunori Matsuzaki
  • Organizer: Scientific Sessions 2008 of American HeartAssociation
  • Place of Presentation: New Orleans
  • Year and Date: 2008-11-08
• [Presentation] 慢性心不全患者における酸化ストレスマーカー : 尿8-hydroxy-2-deoxyguanosine(8-OHdG)の有用性について (2008)
  • Author(s): 小林茂樹,須佐建央,河村修二,田中健雄,伊藤真一,吉賀康裕,岡村誉之,大草知子,矢野雅文,藤井崇史,松崎益徳
  • Organizer: 第105 回日本内科学会総会・講演会
  • Place of Presentation: 東京
  • Year and Date: 2008-04-11
• [Presentation] Urinary8-Hydroxy-2' -Deoxyguanosine LevelReflects Symptomatic Status and Severityof Systolic Dysfunction in Patients withChronic Heart Failure (2008)
  • Author(s): Takehisa Susa, Shigeki Kobayashi, ShujiKawamura, Takeo Tanaka, Shinichi Itoh,Yasuhiro Yoshiga, Takayuki Okamura,Tomoko Ohkusa, Masafumi Yano, TakashiFujii, Masunori Matsuzaki
  • Organizer: The 72nd AnnualScientific Meeting of the JapaneseCirculation Society
  • Place of Presentation: Fukuoka
  • Year and Date: 2008-03-28
• [Presentation] Aldosterone Modulated Gap JunctionRemodeling through MineralocorticoidReceptor (2008)
  • Author(s): Shinsuke Suzuki, Tomoko Ohkusa, TakashiSatoh, Masa-aki Yoshida, Kenji Yasui,Kieko Miwa Jong-kook Lee, Itsuo Kodama,Masafumi Yano, Masunori Matsuzaki
  • Organizer: The 72nd Annual ScientificMeeting of the Japanese CirculationSociety
  • Place of Presentation: Fukuoka
  • Year and Date: 2008-03-28
• [Presentation] アルドステロンの心筋細胞ギャップ結合リモデリングへの影響 (2007)
  • Author(s): 鈴木慎介, 大草知子, 佐藤孝志, 三輪佳子, 李鐘国, 安井健二, 児玉逸雄, 松崎益徳
  • Organizer: 第91回日本循環器学会中国地方会
  • Place of Presentation: 米子
  • Year and Date: 2007-12-01
• [Presentation] カテコラミン誘発性心室頻拍(CPVT)の発生機序としてのリアノジン受容体機能異常 (2007)
  • Author(s): 内海仁志, 矢野雅文, 大野誠, 徐暁娟, 立石裕樹, 小林茂樹, 山本健, 大草知子, 池田安宏, 松崎益徳
  • Organizer: 第91 回日本循環器学会中国地方会
  • Place of Presentation: 米子
  • Year and Date: 2007-12-01
• [Presentation] Urinary 8-Hydroxy-2'-DeoxyguanosineLevel Reflects Symptomatic Status andSeverity of Systolic Dysfunction inPatients with Chronic Heart Failure (2007)
  • Author(s): Takehisa Susa, Shigeki Kobayashi, SyujiKawamura, Shinichi Itoh, Takeo Tanaka,Yasuhiro Yoshiga, Tsuyoshi Ueyama,Takayuki Okamura, Tomoko Ohkusa, MasafumiYano, Takashi Fujii, Masunori Matsuzaki
  • Organizer: Scientific Sessions 2007 of American HeartAssociation
  • Place of Presentation: Orland
  • Year and Date: 2007-11-05
• [Presentation] 学術諮問委員会提言シンポジウム「レニン・アンジオテンシン・アルドステロン系のギャップ結合リモデリングへの関与とupstream 治療について」 (2007)
  • Author(s): 大草知子, 李鐘国, 安井健二, 児玉逸雄, 松崎益徳
  • Organizer: 第24回日本心電学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-10-05
• [Presentation] T 型Ca^<2+>チャネルは心室筋細胞のアルドステロンによるギャップ結合リモデリングを制御する (2007)
  • Author(s): 鈴木慎介, 大草知子, 佐藤孝志, 吉田雅昭, 安井健二, 李鐘国, 三輪佳子, 児玉逸雄, 松崎益徳
  • Organizer: 第24回日本心電学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-10-05
• [Presentation] レニン・アンジオテンシン・アルドステロン系のギャップ結合リモデリングへの関与とupstream治療について (2007)
  • Author(s): 大草 知子
  • Organizer: 第24回日本心電学会学術集会シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2007-10-05
• [Presentation] T型Ca2+チャネルは心室筋細胞のアルドステロンによるギャップ結合リモデリングを制御する (2007)
  • Author(s): 鈴木 慎介
  • Organizer: 第24回日本心電学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-10-05
• [Presentation] The Role of AnserineDuring the Development of Heart Failure inCardiomyopathic Hamster (2007)
  • Author(s): Shinsuke Suzuki, Tomoko Ohkusa, TakashiSato, Fumiyo Ohya, Yoshiharu Matahira,Masunori Matsuzaki
  • Organizer: he 11th Annual Scientific Meeting of theJapanese Heart Failure Society
  • Place of Presentation: Chiba
  • Year and Date: 2007-09-09
• [Presentation] Gap Junction Remodeling Caused byAldosterone is Modulated by Ca^<2+> ChannelActivity (2007)
  • Author(s): Shinsuke Suzuki, Tomoko Ohkusa, TakashiSato, Keiko Miwa,Jong-Kook Lee, KenjiYasui, Itsuo Kodama, Masunori Matsuzaki
  • Organizer: The 11th Annual Scientific Meeting of theJapanese Heart Failure Society
  • Place of Presentation: Chiba
  • Year and Date: 2007-09-09
• [Presentation] DefectiveDomain-Domain Interaction BetweenC-terminal and Central Regions ofRyanodine Receptor as a Critical Cause ofDiastolic Ca^<2+> Spark in CanineCardiomyocytes (2007)
  • Author(s): Hiroki Tateishi, 、Masafumi Yano, MakotoOhno, Xiaojuan Xu, Hitoshi Uchinoumi,Mamoru Mochizuki, Shigeki Kobayashi,Takeshi Yamamoto, Yasuhiro Ikeda, TomokoOhkusa, Masunori Matsuzaki
  • Organizer: The 11th Annual ScientificMeeting of the Japanese Heart FailureSociety
  • Place of Presentation: Chiba
  • Year and Date: 2007-09-09
• [Presentation] SpontaneousCa^2+ Sparks Through Mutated RyanodineReceptor as a Critical Cause ofCatecholaminergic PolymorphicVentricular Tachycardia (2007)
  • Author(s): Hitoshi Uchinoumi, Masafumi Yano,Makoto Ohno, Xiaojuan Xu, Hiroki Tateishi,Mamoru Mochizuki, Shigeki Kobayashi,Takeshi Yamamoto, Yasuhiro Ikeda, TomokoOhkusa, Masunori Matsuzaki
  • Organizer: The 11th AnnualScientific Meeting of the Japanese HeartFailure Society
  • Place of Presentation: Chiba
  • Year and Date: 2007-09-09
• [Presentation] The role of anserine during the development of heart failure in cardiomyopathic hamster (2007)
  • Author(s): Shinsuke Suzuki
  • Organizer: 11^<th> Annual Scientific Meeting of the Japanese Heart Failure Society
  • Place of Presentation: 千葉
  • Year and Date: 2007-09-09
• [Presentation] シンポジウム「結合組織疾患における最近のトピックス」 (2007)
  • Author(s): 大草知子
  • Organizer: 第39回日本結合組織学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-10
• [Presentation] 心筋細胞ギャップ結合リモデリングの頻脈性不整脈への関与 (2007)
  • Author(s): 大草 知子
  • Organizer: 第39回日本結合組織学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-05-10
• [Presentation] アルドステロンによる心筋細胞ギャップ結合リモデリングへのTCCの関与について (2007)
  • Author(s): 大草知子
  • Organizer: 第4回TCCフォーラム
  • Place of Presentation: 東京
  • Year and Date: 2007-04-14
• [Presentation] Young Investigator's Award forInternational Students Finalists Lecture「Decreased affinity of calmodulinbinding to RyR2 may cause leaky channel inCPVT-associated mutation : Insight fromRyR2^<R2474S/+> Knock-in mouse model」 (2007)
  • Author(s): Xiaojuan Xu, Masafumi Yano, TakeshiSuetomi, Makoto Ono, Hitoshi Uchinoumi,Hiroki Tateishi, Shinichi Okuda, ShigekiKobayashi, Takeshi Yamamoto, YasuhiroIkeda, Tomoko Ohkusa, Masunori Matsuzaki
  • Organizer: The 73rd Annual Scientific Meeting of The Japanese Circulation Society
  • Place of Presentation: Osaka
  • Year and Date: 2007-03-20