Elucidation of the role of epigenetic regulation by NRSF complex in maintaining cardiac integrity

• Project/Area Number: 25860596
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: KUWABARA Yoshihiro 京都大学, 医学(系)研究科(研究院), 研究員 (40647400)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 転写因子 / NRSF / 心不全 / エピゲノム / 循環器 / ノックアウトマウス

Outline of Final Research Achievements

In this study, I succeeded to generate cardiac-specific NRSF conditional knockout mice (NRSF ccKO) and found that these mice show cardiac dysfunction, malignant arrhythmias and sudden cardiac death, implying that NRSF plays an essential role in maintaining normal cardiac function. To address the underlying mechanisms, I crossed these mice with HDAC1/2 cardiac-specific double heterozygote knockout mice and analyzed NRSF/HDAC1/2 cardiac-specific triple heterozygote knockout mice. I also found that GNAO1 gene expression is increased in NRSF ccKO. To examine the contribution of G alpha O to cardiac dysfunction seen in NRSF ccKO, I treated these mice with PTX and found that PTX improved cardiac function and the survival curve in NRSF ccKO. Currently I am further analyzing the role of G alpha O in the phenotype of NRSF ccKO.

Research Products

• [Journal Article] Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2 (2015)
  • Author(s): Oshita K, Itoh M, Hirashima S, Kuwabara Y, Ishihara K, Kuwahara K, Nakao K, Kimura T, Nakamura K, Ushijima K, Takano M.
  • Journal Title: J Mol Cell Cardiol Volume: 80 Pages: 81-89
  • DOI: 10.1016/j.yjmcc.2014.12.019
  • NAID: 120006651998
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure (2014)
  • Author(s): Yamada Y, Kinoshita H, Kuwahara K, Nakagawa Y, Kuwabara Y, Minami T, Yamada C, Shibata J, Nakao K, Cho K, Arai Y, Yasuno S, Nishikimi T, Ueshima K, Kamakura S, Nishida M, Kiyonaka S, Mori Y, Kimura T, Kangawa K, Nakao K.
  • Journal Title: Cardiovascular Research Volume: 104 Pages: 183-193
  • DOI: 10.1093/cvr/cvu185
  • NAID: 120005619790
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The effects of super-flux (high performance) dialyzer on plasma glycosylated pro-B-type natriuretic peptide (proBNP) and glycosylated N-Terminal proBNP in end-stage renal disease patients on dialysis (2014)
  • Author(s): Nakagawa Y, Nishikimi T, Kuwahara K, Yasuno S, Kinoshita H, Kuwabara Y, Nakao K, Minami T, Yamada C, Ueshima K, Ikeda Y, Okamoto H, Horii K, Nagata K, Kangawa K, Minamino N, Nakao K.
  • Journal Title: PLOS ONE Volume: 25
  • DOI: 10.1371/journal.pone.0092314
  • NAID: 120006651999
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy. (2013)
  • Author(s): Yasuno, S., Kuwahara, K., Kinoshita, H., Yamada, C., Nakagawa, Y., Usami, S., Kuwabara, Y., Ueshima, K., Harada, M., Nishikimi, T., Nakao, K.
  • Journal Title: Br J Pharmacol Volume: 170(7) Pages: 1384-1395
  • DOI: 10.1111/bph.12328
  • Peer Reviewed
• [Journal Article] Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts (2013)
  • Author(s): Kuwabara, Y., Kuwahara, K., Takano, M., Kinoshita, H., Arai, Y., Yasuno, S., Nakagawa, Y., Igata, S., Usami, S., Minami, T., Yamada, Y., Nakao, K., Yamada, C., Shibata, J., Nishikimi, T., Ueshima, K., Nakao, K.
  • Journal Title: J Am Heart Assoc Volume: 2(3)
  • DOI: 10.1161/jaha.113.000150
  • Peer Reviewed
• [Journal Article] Direct Immunochemiluminescent Assay for proBNP and Total BNP in Human Plasma proBNP and Total BNP Levels in Normal and Heart Failure. (2013)
  • Author(s): Nishikimi, T., Okamoto, H., Nakamura, M., Ogawa, N., Horii, K., Nagata, K., Nakagawa, Y., Kinoshita, H., Yamada, C., Nakao, K., Minami, T., Kuwabara, Y., Kuwahara, K., Masuda, I., Kangawa, K., Minamino, N., Nakao, K.
  • Journal Title: PLoS One Volume: 8(1)
  • DOI: 10.1371/journal.pone.0053233
  • NAID: 120005241437
  • Peer Reviewed
• [Presentation] Increased Expression of HCN channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts (2014)
  • Author(s): Yoshihiro Kuwabara, Koichiro Kuwahara, Makoto Takano, Hideyuki Kinoshita, Yuji Arai, Yasuaki Nakagawa, Shinji Ysuno, Sachiyo Igata, Satoru Usami, Takeya Minami, Yuko Yamada, Kazuhiro Nakao, Chinatsu Yamada, Junko Shibata, Toshio Nishikimi, Kenji Ueshima and Kazuwa Nakao
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術集会
  • Place of Presentation: ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-22 – 2014-07-25
• [Presentation] 左室リモデリング進行及び催不整脈性抑制におけるレニンーアンジオテンシン系の検討 (2013)
  • Author(s): 山田千夏、桑原宏一郎、木下秀之、錦見俊雄、中尾一泰、桒原佳宏、保野慎治、中川靖章、上嶋健治、中尾一和
  • Organizer: 第86回 日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] 肺動脈性肺高血圧症に対する新規治療標的としてのTRPC3/6阻害効果の検討 (2013)
  • Author(s): 木下秀之、桑原宏一郎、清中茂樹、森泰生、赤木達、中村一文、桒原佳宏、中川靖章、錦見俊雄、中尾一和
  • Organizer: 第2回 日本肺循環学会学術集会
  • Place of Presentation: 東京
• [Remarks] 研究室ホームページ
  • URL: http://www.kuhp.kyoto-u.ac.jp/~med2/jpn/research/cardio.html
• [Remarks] 京都大学大学院医学研究科 内分泌代謝内科学 心臓グループ
  • URL: http://www.kuhp.kyoto-u.ac.jp/~med2/jpn/research/cardio.html