Anti-remodeling effect of mitochondrial DNA; A novel approach for the treatment of heart failure using recombinant TFAM

• Project/Area Number: 23591084
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyushu University
• Principal Investigator: IDE Tomomi 九州大学, 医学研究院, 講師 (90380625)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ミトコンドリア / 活性酵素 / 心肥大 / 活性酸素 / NFAT / ミトコンドリアDNA / 心筋肥大 / 酸化ストレス

Research Abstract

The overexpression of mitochondrial transcription factor A (TFAM) attenuates the decrease in mtDNA copy number after myocardial infarction, ameliorates pathological hypertrophy, and markedly improves survival. However, non-transgenic strategy to increase mtDNA for the treatment of pathological hypertrophy remains unknown. We produced recombinant human TFAM protein (rhTFAM). rhTFAM rapidly entered into mitochondria of cultured cardiac myocytes. rhTFAM increased mtDNA and abolished the activation of nuclear factor of activated T cells (NFAT), which is well known to activate pathological hypertrophy. rhTFAM attenuated
subsequent morphological hypertrophy of myocytes as well. rhTFAM would be an attractive molecule in attenuating cardiac pathological hypertrophy.

Research Products

• [Journal Article] Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expression s and pathway activation (2013)
  • Author(s): Onitsuka K, Ide T, Arai S, Hata Y, Murayama Y, Hosokawa K, Sakamoto T, Tobushi T, Sakamoto K, Fujino T, Sunagawa K
  • Journal Title: J Mol Cell Cardiol Volume: 64C Pages: 30-38
• [Journal Article] The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice (2013)
  • Author(s): Tanaka A, Ide T, Fujino T, Onitsuka K, Ikeda M, Takehara T, Hata Y, Ylikallio E, Tyynismaa H, Suomalainen A, Sunagawa K
  • Journal Title: PLoS One Volume: 8
• [Journal Article] Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expression s and pathway activation. (2013)
  • Author(s): Onitsuka K, Ide T, Arai S, Hata Y, Murayama Y, Hosokawa K, Sakamoto T, Tobushi T, Sakamoto K, Fujino T, Sunagawa K.
  • Journal Title: J Mol Cell Cardiol. Volume: 64C Pages: 30-38
  • Peer Reviewed
• [Journal Article] The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice. (2013)
  • Author(s): Tanaka A, Ide T, Fujino T, Onitsuka K, Ikeda M, Takehara T, Hata Y, Ylikallio E, Tyynismaa H, Suomalainen A, Sunagawa K.
  • Journal Title: PLoS One. Volume: 8 Issue: 6 Pages: e67642-e67642
  • DOI: 10.1371/journal.pone.0067642
  • 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, Sunagawa K
  • Journal Title: Mitochondrion Volume: 12 Pages: 449-458
• [Journal Article] Recombinant mi tochondnal transcript ion factor A protein inhibits niclear factor of activated T cells signaling and attenuates (2012)
  • Author(s): Fujino T., et al
  • Journal Title: Mitochondrion Volume: 4 Issue: 4 Pages: 449-458
  • DOI: 10.1016/j.mito.2012.06.002
  • Peer Reviewed
• [Presentation] The Increase of Mitochondrial DNA Copy Number Attenuates Eccentric Cardiac Remodeling in Volume Overload Model Circ J. 77(SupplI): 425 (2013)
  • Author(s): Masataka Ikeda ,Tomomi Ide ,Takeo Fujino ,Ken Onitsuka ,Tomoyuki Tobushi ,Kazuo Sakamoto ,Keita Saku ,Takamori Kakino ,Henna Tyynismaa ,Hiroyuki Tsutsui ,Anu Suomalainen ,Kenji Sunagawa
  • Organizer: 2013第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Increased Mitochondrial DNA Copy Number Attenuates Excessive Mitochondrial Reactive Oxygen Species and Inhibits NFAT Signaling in Cardiac Myocytes. Circulation Journal 2013; 77 (Suppl. I): I-952 (2013)
  • Author(s): Fujino T, Ide T, Ikeda M, Onitsuka K, Hata Y, Takehara T, Sakamoto K, Tobushi T, Saku K, Kakino T, Sunagawa K
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] The Overexpression of Mitochondrial Transcription Factor A Attenuates Mitochondrial Reactive Oxygen Species Generation and Inhibits Pathological Remodeling in Cardiac Myocytes (2013)
  • Author(s): Fujino T, Ide T, Ikeda M, Onitsuka K, Hata Y, Takehara T, Sakamoto K, Tobushi T, Saku K, Sunagawa K
  • Organizer: 日本心不全学会
  • Place of Presentation: (Journal of Cardiac Failure 2012; 18 (10S): S170)
• [Presentation] ベッドサイドとラボで学んだ心筋症 (2013)
  • Author(s): 井手友美
  • Organizer: 東京心臓病理フォーラム
  • Place of Presentation: 東京
  • Invited
• [Presentation] どこまで高尿酸血症を治療すべきか ～酸化ストレスと尿酸との関係～ (2013)
  • Author(s): 井手友美
  • Organizer: 第8回 高尿酸血症フォーラム in 久留米内科医会
  • Place of Presentation: 久留米
  • Invited
• [Presentation] Increased Mitochondrial DNA Copy Number Attenuates Excessive Mitochondrial Reactive Oxygen Species and Inhibits NFAT Signaling in Cardiac Myocytes. (2013)
  • Author(s): Fujino T et al
  • Organizer: 第77回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜
• [Presentation] The Increase of Mitochondrial DNA Copy Number Attenuates Eccentric Cardiac Remodeling in Volume Overload Model (2013)
  • Author(s): Imeda M et al
  • Organizer: 第77回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜
• [Presentation] 新たな心筋リモデリング制御のターゲットとしてのミトコンドリアDNAに関する研究 (2013)
  • Author(s): 井手 友美
  • Organizer: 第86会日本薬理学会学術集会
  • Place of Presentation: 福岡
• [Presentation] The increase of Mitochondrial DNA Copy Number Attenuates Eccentric Cardiac Remodeling in Volume Overload Model (2012)
  • Author(s): Masataka Ikeda, Tomomi Ide, Takeo Fujino, Yuko Hata, Takako Takehara, Ken Onitsuka, Tomoyuki Tobushi, Kazuo Sakamoto, Keita Saku, Takamori Kakino, Kenji Sunagawa
  • Organizer: 第29回国際心臓研究会日本部会総会
  • Place of Presentation: 福岡
• [Presentation] The Increase of Mitochondrial DNA Copy Number Attenuates Mitochondrial Reactive Oxygen Species Generation and Inhibits Pathological Remodeling in Cardiac Myocytes (2012)
  • Author(s): Fujino T, Ide T, Ikeda M, Onitsuka K, Hata Y, Takehara T, Sakamoto K, Tobushi T, Saku K, Kakino T, Sunagawa K
  • Organizer: 第29回国際心臓研究会日本部会総会
  • Place of Presentation: 福岡
• [Presentation] Phase Targeted Dynamic Load of Left Ventricle Induces Distinct Phase Sensitive Gene Expressions and Pathway Activation (2012)
  • Author(s): Ken Onitsuka, Tomomi Ide, Shinobu Arai, Yuko Hata, Takako Takehara, Yoshinori Murayama, Kazuo Sakamoto, Tomoyuki Tobushi, Takeo Fujino, Keita Saku, Masataka Ikeda, Takamori Kakino, Kenji Sunagawa
  • Organizer: 第29回国際心臓研究会日本部会総会
  • Place of Presentation: 福岡
• [Presentation] The Overexpression of Mitochondrial Transcription Factor A Attenuates Mitochondrial Reactive Oxygen Species Generation and Inhibits Pathological Remodeling in Cardiac Myocytes (2012)
  • Author(s): Fujino T et al
  • Organizer: 第16回日本心不全学会学術集会
  • Place of Presentation: 仙台
• [Presentation] The Increase of Mitochondrial DNA Copy Number Attenuates Mitochondrial Reactive Oxygen Species Generation and Inhibits Pathological Remodeling in Cardiac Myocytes. (2012)
  • Author(s): Fujino T et al
  • Organizer: 第29回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: 福岡
• [Presentation] Phase Targeted Dynamic Load of Left Ventricle Induces Distinct Phase Sensitive Gene Expressions and Pathway Activation (2012)
  • Author(s): Onitsuka K et al
  • Organizer: 第29回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: 福岡
• [Presentation] ミトコンドリアDNA量と生体ホメオスターシスの維持に関するマウスモデルによる検討 (2011)
  • Author(s): 井手 友美
  • Organizer: 第84会日本生化学会大会(招待講演)
  • Place of Presentation: 京都
• [Presentation] Recombinant mitochondrial transcriptional factor A protein attenuates pathological remodeling in cardiac myocytes (2011)
  • Author(s): 藤野剛雄 井手友美 砂川賢二
  • Organizer: Experimental Biology 2011
  • Place of Presentation: Washington DC, USA
• [Presentation] Recombinant Tfam attenuates Pathological Remodeling in Cardiac Myocytes via Inhibiting NFat Signaling (日本酸化ストレス学会YIA受賞) (2011)
  • Author(s): 藤野剛雄 井手友美 砂川賢二
  • Organizer: 日本ミトコンドリア学会 5th SFRR-ASIA 8th ASMRM 11th J-mit
  • Place of Presentation: 鹿児島
• [Presentation] Recombinant mitochondrial transcriptional factor A protein attenuates pathological remodeling in cardiac myocytes (2011)
  • Author(s): 藤野剛雄 井手友美 砂川賢二
  • Organizer: 米国心臓病学会2011
  • Place of Presentation: Orlando, USA