心臓特異的「自然炎症」とその破綻機構:非感染性炎症疾患"心房細動"での検討

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 22117507
• 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: Tokyo Medical and Dental University
• Principal Investigator: 古川 哲史 東京医科歯科大学, 難治疾患研究所, 教授 (80251552)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000); Fiscal Year 2011: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 慢性炎症 / 心房細動 / マクロファージ / ATP / Toll様受容体 / 活性酸素 / TRPチャネル / ギャップ結合チャネル / 自然炎症 / インフラマゾーム / 活性酸素種

Research Abstract

申請段階で3つの達成目標を立てた。これらについて今年度の研究成果を記述する。
(1)ATP/プリン受容体に関する検討:心房細動では、リスク因子と心房細動の間に慢性炎症が関与することが示唆されている。リスク因子の中で最も頻度の多い心房筋伸展と慢性炎症の関連について検討した。In vitroおよびin vivo実験で、心房筋の伸展によりマクロファージの遊走が誘導され、心房の線維化、心房細動の誘発性が上昇した。マクロファージの遊走にはATPが関与すること、ATPは心房筋の伸展によりギャップ結合チャネルを介して放出されることが明らかとなった。In vivoで心房伸展により誘導されるマクロファージの浸潤、心房線維化、心房細動の誘発は、ギャップ結合チャネルの投与により抑制された。
(2)FFA・LPS/TLR4に関する検討:FFA・LPS投与によりマクロファージの心房への浸潤、心房の線維化が誘導されることが確認された。そこで、野生型マウス(WT)とTLR4 KOマウスで、FFA・LPS投与によるこれらの変化を検討したところ、両者で差がなかった。この検討がネガティブデータであったことから、心房伸展によるマクロファージ浸潤・心房線維化に対する作用も検討したが、やはりWTマウスとTLR4 KOマウス間で有意差を認めなかった。心房における炎症では、TLR4は大きな役割を果たしていないことが示唆された。
(3)ROS/TRPチャネルに関する検討:LPS刺激によりマクロファージにおけるサイトカインの産生・分泌が増加することが確認された。この作用は、細胞内Ca^<2+>濃度上昇を伴っており、TRPチャネルブロッカー、TRPチャネルのsiRNAによるノックダウンで抑制されることから、LPSによるTRPチャネルの活性化、これに伴う細胞内Ca^<2+>上昇がサイトカイン産生に関わることが明らかとなった。

Research Products

• [Journal Article] Region- and condition-dependence of the membrane and Ca2+ clocks in the sinus node (2012)
  • Author(s): Kurokawa J, Furukawa T
  • Journal Title: Circulation Journal Volume: 76 Pages: 293-294
  • NAID: 10030035264
  • Peer Reviewed
• [Journal Article] Circulating KCNH2 current-activating factor in patients with heart failure and ventricular tachyarrhythmia (2011)
  • Author(s): Siguyama H, Nakamura K, Morita H, Akagi S, Tani Y, Katayama Y, Nishii N, Miyoshi T, Nagase S, Kohno K, Kusano FK, Ohe T, Kurokawa J, Furukawa T, Ito H
  • Journal Title: PLoS ONE Volume: 6
  • Peer Reviewed
• [Journal Article] Atrial fibrillation and inflammation (2011)
  • Author(s): Furukawa T, Oishi S, Sasano T
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 138 Pages: 192-195
  • NAID: 10029896339
• [Journal Article] Role of transient receptor potential vanilloid 2 in LPS-induced cytokine production in macrophages. (2010)
  • Author(s): Yamashiro K, Sasano T, Tojo K, Namekata I, Kurokawa J, Sawada N, Suganami T, Kamei Y, Tanaka H, Tajima N, Utsunomiya K, Ogawa Y, Furukawa T.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 400 Pages: 284-289
  • Peer Reviewed
• [Journal Article] Nitric oxide and cardiac action potential (2010)
  • Author(s): Kurokawa J, Asada K, Furukawa T
  • Journal Title: Nippon Yakurigaku Zasshi Volume: 135 Pages: 95-98
  • NAID: 10026334831
• [Journal Article] Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias : a simulation study (2010)
  • Author(s): Yang PC, Kurokawa J, Furukawa T, Clancy CE
  • Journal Title: PLoS Comput.Biol. Volume: 29
  • Peer Reviewed
• [Journal Article] Transmural dispersion of repolarization and drug-induced Torsade de Pointes-A 3-D simulation study- (2010)
  • Author(s): Furukawa T
  • Journal Title: Circ.J. Volume: 75 Pages: 49-50
  • NAID: 10027425315
  • Peer Reviewed
• [Journal Article] A new echocardiographic method for identifying vortex flow in the left ventricle : numerical validation (2010)
  • Author(s): Uejima T, Koike A, Sawada H, Aizawa T, Ohtsuki S, Tanaka M, Furukawa T, Fraser AG
  • Journal Title: Ultrasound Med.Biol. Volume: 36 Pages: 772-788
  • Peer Reviewed
• [Presentation] ヒトiPS由来心筋の電気生理学的性質におよぼす分化誘導時間の影響 (2012)
  • Author(s): 黒川洵子、遠山周吾、村田光繁、古川哲史、福田恵一
  • Organizer: 第132回日本薬学会年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] Atrial fibrillation-associated locus 4q25 has the cis-regulatory function toward the neighboring PITX2 gene (2012)
  • Author(s): Ebana Y, Ozaki K, Tanaka T, Isobe M, Furukawa T
  • Organizer: The 76^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-18
• [Presentation] A variant in locus of caveolin 1 confers atrial fibrillation anf left atrial enlargement (2012)
  • Author(s): Ebana Y, Makita S, Hirao K, Arai H, Isobe M, Furukawa T
  • Organizer: The 76^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-18
• [Presentation] Genetic deletion of Nos1ap enhanced cardiac impairment and death on oxidative stress induced by doxorubicin (2012)
  • Author(s): Sasano T, Tsuchiya J, Okamura T, Katou N, Hirao K, Isobe M, Furukawa T
  • Organizer: The 76^<th> Annual Scientitic Meeting of the Japanese Circulation Society
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-18
• [Presentation] Scna1a mutant knock-in mouse revealed sudden unexpected death in epilepsy (SUDEP) in Dravet syndrome as cardiac arrhythmia origin (2012)
  • Author(s): Sasano T, Horigome Y, Koizumi A, Takahashi Y, Ogiwara I, Furukawa T
  • Organizer: The 76^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-18
• [Presentation] Polymorphisms on atrial fibrillation-associated locus 4q25 could accelerate the disease onset and the recurrence after pulmonary vein isolation (2012)
  • Author(s): Ebana Y, Hachiya H, Inaba O, Nitta J, Swawabe M, Nogami A, Takahashi A, Nakamura H, Hirao K, Isobe M, Furukawa T
  • Organizer: The 76^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 福岡
  • Year and Date: 2012-03-17
• [Presentation] 心筋L型カルシウム電流に対するジヒドロテストステロンの非ゲノム作用の性差に対する交感神経系刺激の関与 (2012)
  • Author(s): Fernando Lopez-Redondo, 黒川洵子、古川哲史
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-14
• [Presentation] ATP放出抑制はマウス圧負荷モデル心房における催不整脈性を抑制する (2012)
  • Author(s): 大石咲子、笹野哲郎、古川哲史
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-14
• [Presentation] マウス胎児心臓における冠血管走行の性差 (2011)
  • Author(s): 児玉昌美、萩原理生、有馬勇一郎、西山功一、栗原裕基、古川哲史、黒川洵子
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] Stretch-induced ATP release from atrial myocytes as a trigger of inflammation and atrial tachyarrhythmias (2011)
  • Author(s): Furukawa T, Oishi S, Sasano T
  • Organizer: The 28^<th> Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2011-12-02
• [Presentation] Genetics deletion of transcription factor in cardiac conduction system mimicked early repolarization syndrome in mouse (2011)
  • Author(s): Sasano T, Koizumi A, Kimura W, Miura N, Hirao K, Isobe M, Furukawa T
  • Organizer: The 28^<th> Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京
  • Year and Date: 2011-12-02
• [Presentation] NOS1AP deletion enhanced ventricular arrhythmogenicity and cardiac death in pressure overloaded conduction (2011)
  • Author(s): Sasano S, Hirao K, Okamura T, Kato N, Isobe M, Furukawa T
  • Organizer: The 28^<th> Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京
  • Year and Date: 2011-12-02
• [Presentation] Hyperthermia-induced arrhythmias and sudden death in mouse model of Dravet syndrome (2011)
  • Author(s): Sasano T, Horigome Y, Takahashi Y, Ogiwara I, Isobe M, Furukawa T
  • Organizer: The 28^<th> Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京
  • Year and Date: 2011-12-02
• [Presentation] Hyperthermia-induced ventricular tachycardia and sudden cardiac death in mouse model of Dravet syndrome (2011)
  • Author(s): Sasano T, Horigome Y, Takahashi Y, Ogiwara I, Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡
  • Year and Date: 2011-09-22
• [Presentation] Genetic risks of atrial fibrillation in Japan (2011)
  • Author(s): Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡(招待講演)
  • Year and Date: 2011-09-21
• [Presentation] A variant in locus of caveolin 1 confers atrial fibrillation and left atrial enlargement (2011)
  • Author(s): Kishihara Y, Ebana Y, Hachiya H, Hirao K, Isobe M, Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡
  • Year and Date: 2011-09-21
• [Presentation] Non-genomic regulation of K+ and Ca2+ channels by sex hormones (2011)
  • Author(s): Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡(招待講演)
  • Year and Date: 2011-09-20
• [Presentation] J wave syndrome-early repolarization or delayed depolarization? (2011)
  • Author(s): Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡(招待講演)
  • Year and Date: 2011-09-20
• [Presentation] Atrial fibrillation-associated locus 4q25 has the cis-regulatory function toward the neighboring genes (2011)
  • Author(s): Ebana Y, Hachiya H, Hirao K, Isobe M, Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡
  • Year and Date: 2011-09-20
• [Presentation] NOS1AP destruction enhanced susceptibility to oxidative stress in doxorubicin-induced cardiomyopathy (2011)
  • Author(s): Tsuchiya J, Sasano T, Okamura T, Kato N, Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡
  • Year and Date: 2011-09-20
• [Presentation] Genetic destruction of transcription factor in His-Purkinje system mimicked J wave syndrome in mouse (2011)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miura N, Furukawa T
  • Organizer: 4^<th> Asia Pacific Heart Rhythm Society scientific Session (APHRS 2011), 26^<th> Annual Scientific Session of the Japanese Heart Rhythm Society, 28^<th> Annual Scientific Session of the Japanese Society of Electrophysiology
  • Place of Presentation: 福岡
  • Year and Date: 2011-09-19
• [Presentation] Electrophysiological characterization of cardiomyocyte-like cells differentiated from human iPS cells (2011)
  • Author(s): Furukawa T
  • Organizer: The 75^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-08-04
• [Presentation] Extracellular ATP released through pannexin-2 mediates infiltration of macrophage in stretched atrium (2011)
  • Author(s): Sasano T, Oishi S, Furukawa T
  • Organizer: The 75^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜
  • Year and Date: 2011-08-04
• [Presentation] Contribution of Irx3 in His-Purkinje system (HPS) condution and arrhythmogeneity-A possible animal model for HPS-oriented arrhythmias (2011)
  • Author(s): Koizumi A, Sasano T, Miura N, Furukawa T
  • Organizer: The 75^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜
  • Year and Date: 2011-08-04
• [Presentation] Genetic deletion of NOS1AP sensitized to sudden cardiac death ater trasnverse aortic constriction (2011)
  • Author(s): Sasano T, Matsubara S, Tamura S, Isobe M, Furukawa T
  • Organizer: The 75^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜
  • Year and Date: 2011-08-03
• [Presentation] hERGを標的とする薬物安全性評価システムの問題点と対策 (2011)
  • Author(s): 古川哲史
  • Organizer: 第38回日本トキシコロジー学術年会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-07-13
• [Presentation] Characterization of human induced pluripotent stem cell-derived cardiomyocytes (2011)
  • Author(s): 李敏、黒川洵子、諫田泰成、関野祐子、古川哲史
  • Organizer: 第124回日本薬理学会関東部会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-04
• [Presentation] 心房進展における細胞外ATPのオートクライン作用を介した炎症メカニズム (2010)
  • Author(s): 笹野哲郎、大石咲子、田村典子、磯部光章、古川哲史
  • Organizer: 第27回日本心電学会学術集会
  • Place of Presentation: 大分
  • Year and Date: 2010-10-09
• [Presentation] 臨床医のための心臓生理・心臓薬理学 (2010)
  • Author(s): 古川哲史
  • Organizer: 第27回日本心電学会学術集会
  • Place of Presentation: 大分
  • Year and Date: 2010-10-09
• [Presentation] ラウンドテーブルディスカッション「心電現象と性差-不整脈診療に性差の視点を活かす-」心電現象の性差:分子レベルでどこまで分かっているのか? (2010)
  • Author(s): 古川哲史
  • Organizer: 第27回日本心電学会学術集会
  • Place of Presentation: 大分
  • Year and Date: 2010-10-08
• [Presentation] iPS細胞由来心筋細胞の薬物安全性評価への応用 (2010)
  • Author(s): 古川哲史
  • Organizer: 心電学フロンティア2010(第45回理論心電図研究会)
  • Place of Presentation: 大分
  • Year and Date: 2010-10-08
• [Presentation] Autocrine/paracrine mechanisms for macrophage migration evoked by mechanical stretch of atrial myocytes (2010)
  • Author(s): 笹野哲郎、大石咲子、古川哲史
  • Organizer: 13^<th> Tokyo-Taipei-Seoul Arrhythmias Conference
  • Place of Presentation: 福岡
  • Year and Date: 2010-10-02
• [Presentation] イオンチャネル・受容体の細胞膜上での局在と機能 (2010)
  • Author(s): 古川哲史
  • Organizer: 第25回犬山不整脈カンファレンス
  • Place of Presentation: 名古屋
  • Year and Date: 2010-08-21
• [Presentation] イオンチャネル・不整脈と心臓発生・分化 (2010)
  • Author(s): 古川哲史
  • Organizer: 第9回心臓血管発生研究会特別シンポジウム
  • Place of Presentation: 千葉
  • Year and Date: 2010-07-10
• [Presentation] Non-genomic regulation of cardiac ion currents by sex hormones (2010)
  • Author(s): Furukawa T, Nakamura H, Kurokawa J, Sasano T, Isobe M
  • Organizer: XX World Congress JSHR
  • Place of Presentation: 京都
  • Year and Date: 2010-05-16
• [Presentation] 性ホルモンのQT延長に及ぼす作用と不整脈シミュレーション (2010)
  • Author(s): 黒川洵子、中村浩章、Colleen E.Clancy, 古川哲史
  • Organizer: 第112回日本薬理学会関東部会ミニシンポジウム
  • Place of Presentation: 静岡
  • Year and Date: 2010-05-16
• [Presentation] NOS1APノックアウトマウスにおけるQT間隔及び催不整脈性の検討 (2010)
  • Author(s): 松原清二、笹野哲郎、江花有亮、古川哲史、磯部光章
  • Organizer: 第25回日本不整脈学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Risk and mechanism for sudden cardiac death in NOS1AP knockout mice (2010)
  • Author(s): 松原清二、笹野哲郎、江花有亮、古川哲史、磯部光章
  • Organizer: 第14回日本心不全学会
  • Place of Presentation: 東京
• [Presentation] 心不全患者における血清中KCNH2電流活性化因子 (2010)
  • Author(s): 杉山洋樹、中村一文、黒川洵子、古川哲史、森田宏、草野研吾、大江透、伊藤浩
  • Organizer: 第14回日本心不全学会
  • Place of Presentation: 東京
• [Book] 目からウロコの心電図 (2011)
  • Author(s): 古川哲史
  • Total Pages: 129
  • Publisher: ライフメディコム