心房伸展において、炎症が心房リモデリングを惹起するメカニズムの包括的解明

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25461045
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 笹野 哲郎 東京医科歯科大学, その他の研究科, 准教授 (00466898)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 心房細動 / 細胞外ATP / マイクロRNA / 高脂肪食 / 糖尿病 / 圧負荷 / メタボリック症候群 / ギャップジャンクション

Outline of Annual Research Achievements

心房細動は、心房伸展や炎症を契機として心房の電気生理学的・組織学的な変化が生じることにより発症する。この変化を心房リモデリングと呼ぶが、心房伸展に加え、メタボリック症候群や糖尿病なども心房リモデリング促進因子であると考えられている。これらの因子と心房リモデリングについて、マイクロRNA(miR)の関与を中心に検討を行った。

1.メタボリック症候群モデルマウス(HFDモデル)を作成して、心房の電気生理学的変化を中心に詳細な検討を行い、HFDモデルマウスでは心房の伝導速度が低下していること、プログラム刺激によって心房頻拍が高率に誘発されることが明らかとなった。このHFDモデル心房においてはmiR-27bの発現が亢進していた。miR-27bが制御する遺伝子として心房の細胞間伝導に寄与するギャップジャンクションチャネル(Cx40)を同定した。Cx40の発現はHFDモデル心房で低下しており、培養細胞を用いてパルミチン酸負荷を行った検討でもmiR-27bを介したCx40の発現低下が示された。以上より、HFDにおける心房細動発症にはmiR-27bが関与していると考えられた。
2.心房におけるマイクロRNA発現変化の網羅的解析：心房圧負荷モデルマウスを作成し、HFDモデル・糖尿病モデルと共に、心房でのmiRの発現を網羅的に解析した。約750のマイクロRNAの発現を定量し、共通して変化しているmiRを同定し、それらについて、心房の組織的リモデリングに関与する遺伝子の候補を探索した。
3. 臨床例におけるマイクロRNAの網羅的解析：発作性・持続性心房細動患者および健常者の血清より、マイクロRNAの発現を網羅的に解析した。一部のマイクロRNAがマウス心房で発現変化していたものと一致し、心房リモデリング進行のバイオマーカーとなる可能性が示された。

Research Products

• [Journal Article] High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b (2016)
  • Author(s): Takahashi K, Sasano T, Sugiyama K, Kurokawa J, Tamura N, Soejima Y, Sawabe M, Isobe M, Furukawa T.
  • Journal Title: J Mol Cell Cardiol. Volume: 90 Pages: 38-46
  • DOI: doi: 10.1016/j.yjmcc.2015.11.034.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Heterozygous deletion of sarcolipin maintains normal cardiac function. (2016)
  • Author(s): Shimura D, Kusakari Y, Sasano T, Nakashima Y, Nakai G, Jiao Q, Jin M, Yokota T, Ishikawa Y, Nakano A, Goda N, Minamisawa S.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 310 Pages: H92-103
  • DOI: doi: 10.1152/ajpheart.00411.2015.
  • Peer Reviewed
• [Journal Article] Intravital imaging of Ca2+ signals in lymphocytes of Ca2+ biosensor transgenic mice: indication of autoimmune diseases before the pathological onset (2016)
  • Author(s): Yoshikawa S, Usami T, Kikuta J, Ishii M, Sasano T, Sugiyama K, Furukawa T, Nakasho E, Takayanagi H, Tedder TF, Karasuyama H, Miyawaki A, Adachi T.
  • Journal Title: Scientific Reports Volume: 6 Pages: 18738
  • DOI: 10.1038/srep18738
  • Peer Reviewed / Open Access
• [Journal Article] Oxidative Stress Induced Ventricular Arrhythmia and Impairment of Cardiac Function in Nos1ap Deleted Mice. (2016)
  • Author(s): Sugiyama K, Sasano T, Kurokawa J, Takahashi K, Okamura T, Kato N, Isobe M and Furukawa T
  • Journal Title: Int Heart J. Volume: 57 Pages: 000-000
  • DOI: http://doi.org/10.1536/ihj.15-471
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. (2016)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N and Furukawa T.
  • Journal Title: Eur Heart J. Volume: 37 Pages: 1469-75
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed
• [Journal Article] 心房頻拍モデルマウスおよび心房細動患者における、心房炎症とマイクロRNA発現の網羅的解析 (2015)
  • Author(s): 笹野 哲郎、古川 哲史
  • Journal Title: 循環器専門医 Volume: 23 Pages: 202-9
• [Presentation] Selective assessment of left atrial activation and conduction disturbance using a high-sensitive vector magnetocardiography. (2016)
  • Author(s): Natsume Y, Hasegawa Y, Nishimura T, Sasaki T, Shirai Y, Kawabata M, Kawabata S, Adachi Y, Sumi Y, Goya M, Hirao K, Sasano T
  • Organizer: Heart Rhythm Society meeting
  • Place of Presentation: Moscone Center, San Francisco, USA
  • Year and Date: 2016-05-05 – 2016-05-05
  • Int'l Joint Research
• [Presentation] Multichannel measurement of P wave fragmentations by high-sensitive vector magnetocardiography can evaluate the conduction disturbance in left atrium. (2016)
  • Author(s): Hasegawa Y, Natsume Y, Shirai Y, Nishimura T, Sasaki T, Kawabata M, Kawabata S, Sumi Y, Goya M, Hirao K, Sasano T
  • Organizer: Heart Rhythm Society meeting
  • Place of Presentation: Moscone Center, San Francisco, USA
  • Year and Date: 2016-05-05 – 2016-05-05
  • Int'l Joint Research
• [Presentation] Genetic deletion of Nos1ap induced ventricular arrhythmia and impairment of cardiac function under oxidative stress condition. (2016)
  • Author(s): Sasano T, Sugiyama K, Kurokawa J, Takahashi K, Okamura T, Kato N, Isobe M, Furukawa T
  • Organizer: 5th International Conference of Cardiovascular Medicine
  • Place of Presentation: China Medical University, Taichung, Taiwan
  • Year and Date: 2016-03-05 – 2016-03-05
  • Int'l Joint Research / Invited
• [Presentation] IRX3, a His-Purkinje system specific transcription factor is related with ventricular tachyarrhythmia. (2015)
  • Author(s): Sasano T, Koizumi A, Kimura W, Nogami A, Fukamizu S, Sakurada H, Hirao K, Isobe M, Kimura A, Aiba T, Miyamoto Y, Shimizu W, Miura N, Furukawa T
  • Organizer: Asia-pacific Heart Rhythm Society meeting
  • Place of Presentation: Melbourne Convention and Exhibition Centre, Melbourne, Australia
  • Year and Date: 2015-11-22 – 2015-11-22
  • Int'l Joint Research / Invited
• [Presentation] Comprehensive analysis identifies common microRNA expression involved in murine models of atrial remodeling and clinical specimen (2015)
  • Author(s): Sasano T, Takahashi K, Ihara K, Sugiyama K, Nishimura T, Shirai Y, Tao S, Sasaki T, Kawabata M, Goya M, Hirao K, Isobe M, Furukawa T
  • Organizer: Asia-pacific Heart Rhythm Society meeting
  • Place of Presentation: Melbourne Convention and Exhibition Centre, Melbourne, Australia
  • Year and Date: 2015-11-22 – 2015-11-22
  • Int'l Joint Research
• [Presentation] Oxidative stress induced ventricular arrhythmias and impaired cardiac function in Nos1ap deleted mice. (2015)
  • Author(s): Sugiyama K, Sasano T, Tamura N, Okamura T, Kato N, Isobe M, Frukawa T
  • Organizer: Asia-pacific Heart Rhythm Society meeting
  • Place of Presentation: Melbourne Convention and Exhibition Centre, Melbourne, Australia
  • Year and Date: 2015-11-21 – 2015-11-21
  • Int'l Joint Research
• [Presentation] Number of P wave fragmentations measured by vector magnetocardiography may evaluate conduction disturbance in left atrium. (2015)
  • Author(s): Hasegawa Y, Natsume Y, Nishimura T, Shirai Y, Tao S, Sasaki T, Kawabata M, Sumi Y, Goya M, Isobe M, Hirao K, Sasano T
  • Organizer: Asia-pacific Heart Rhythm Society meeting
  • Place of Presentation: Melbourne Convention and Exhibition Centre, Melbourne, Australia
  • Year and Date: 2015-11-20 – 2015-11-20
  • Int'l Joint Research
• [Presentation] Novel Dielectric Blood Coagulometry Can Evaluate Factor Xa Activity and Reduced Coagulability by Dalteparin. (2015)
  • Author(s): Hamada S, Hasegawa Y, Nishimura T, Sumi Y, Koyama T, Furukawa T, Hirao K, Sasano T
  • Organizer: Asia-pacific Heart Rhythm Society meeting
  • Place of Presentation: Melbourne Convention and Exhibition Centre, Melbourne, Australia
  • Year and Date: 2015-11-20 – 2015-11-20
  • Int'l Joint Research
• [Presentation] Detection of pulmonary venous activity utilizing high-sensitive vector magnetocardiography. (2015)
  • Author(s): Sasano T, Oya M, Hasegawa Y, Terui M, Adachi Y, Hirao K
  • Organizer: Asian Symposium of magnetocardiography
  • Place of Presentation: Korea Research Institute of Standards and Science, Daejeon, Korea
  • Year and Date: 2015-11-02 – 2015-11-02
  • Int'l Joint Research / Invited
• [Presentation] J波と心臓MRIにおける遅延造影との関連性の検討および川崎病におけるJ波の頻度 (2015)
  • Author(s): 澤田 由梨子、宇佐 知里郁、小山 望、角 勇樹、寺島 正浩、平尾 見三、磯部 光章、笹野 哲郎
  • Organizer: 日本不整脈学会・心電学会合同学術集会
  • Place of Presentation: 国立京都国際会館、京都府京都市
  • Year and Date: 2015-07-31 – 2015-07-31
• [Presentation] Nocturnal Variations in Atrial and Ventricular Electrophysiological Properties in Obstructive Sleep Apnea. (2015)
  • Author(s): Sasano T, Ishihara Y, Oya M, Fujie T, Tamaoka M, Sumi Y, Matsuura M, Miyazaki Y, Hirao K
  • Organizer: 日本不整脈学会・心電学会合同学術集会
  • Place of Presentation: 国立京都国際会館、京都府京都市
  • Year and Date: 2015-07-31 – 2015-07-31
• [Presentation] 指尖容積脈波を用いた末梢血管自律神経機能評価 (2015)
  • Author(s): 濱田 里美、石原 有理、井上 芳徳、磯部 光章、平尾 見三、笹野 哲郎
  • Organizer: 日本不整脈学会・心電学会合同学術集会
  • Place of Presentation: 国立京都国際会館、京都府京都市
  • Year and Date: 2015-07-30 – 2015-07-30
• [Presentation] Filtered P Wave Duration by Vector Magnetocardiography may Evaluate Conduction Disturbance in Left Atrium. (2015)
  • Author(s): Hasegawa Y, Hamada S, Nishimura T, Shirai Y, Tao S, Sasaki T, Kawabata M, Goya M, Sumi Y, Isobe M, Hirao K, Sasano T
  • Organizer: 日本不整脈学会・心電学会合同学術集会
  • Place of Presentation: 国立京都国際会館、京都府京都市
  • Year and Date: 2015-07-29 – 2015-07-29
• [Presentation] 高感度ベクトル心磁図による肺静脈周囲心筋興奮の検出 (2015)
  • Author(s): 笹野 哲郎、大矢 麻美子、長谷川 由貴、照井 まりな、川端 茂徳、足立 善昭、平尾 見三
  • Organizer: 第31回日本生体磁気学会
  • Place of Presentation: 旭川市大雪クリスタルホール、北海道旭川市
  • Year and Date: 2015-06-06 – 2015-06-06
  • Invited
• [Presentation] Novel dielectric coagulometer identifies the increased coagulability in patients with high CHADS2 score. (2015)
  • Author(s): Hasegawa Y, Hamada S, Nishimura T, Shirai Y, Tao S, Sasaki T, Kawabata M, Goya M, Isobe M, Koyama T, Sumi Y, Hirao K, Sasano T
  • Organizer: Heart Rhythm Society meeting
  • Place of Presentation: Boston Convention & Exhibition Center, Boston, USA
  • Year and Date: 2015-05-15 – 2015-05-15
  • Int'l Joint Research
• [Presentation] Nocturnal Variation of P-wave Signal Averaged Electrocardiogram Parameters in Obstructive Sleep Apnea Patients. (2015)
  • Author(s): Ishihara Y, Kono A, Oya M, Fujie T, Tamaoka M, Matsuura M, Sumi Y, Miyazaki Y, Isobe M, Hirao K, Sasano T.
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪国際会議場、大阪府大阪市
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Comprehensive Analysis Linking MicroRNA and Atrial Inflammation in Mouse and Human. (2015)
  • Author(s): Sasano T, Takahashi K, Zhang P, Ihara K, Sugiyama K, Tamura N, Nishimura T, Shirai Y, Tao S, Sasaki T, Kawabata M, Goya M, Hirao K, Isobe M, Furukawa T
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪国際会議場、大阪府大阪市
  • Year and Date: 2015-04-24 – 2015-04-24
• [Presentation] High-Fat Diet Increases Vulnerability to Atrial Arrhythmia by Conduction Disturbance via MicroRNA. (2015)
  • Author(s): Takahashi K, Sasano T, Sugiyama K, Isobe M, Furukawa T
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪国際会議場、大阪府大阪市
  • Year and Date: 2015-04-24 – 2015-04-24