Exploring the novel compounds targeting dysregulated autophagy-mediated cardiac dysfunction

• Project/Area Number: 15H04817
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ISOBE Mitsuaki 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (80176263)
• Co-Investigator(Kenkyū-buntansha): 前嶋 康浩 東京医科歯科大学, 医学部附属病院, 助教 (40401393) ; 秦野 雄 東京医科歯科大学, 医学部附属病院, 助教 (00736407)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: オートファジー / 心不全 / 循環器・高血圧 / シグナル伝達 / バイオテクノロジー / デスミン心筋症

Outline of Final Research Achievements

Based on our previous result that cardiac function is mediated through suppression of autophagy by phosphorylating Beclin1 by Mst1, we explored novel low molecular compounds which can competitively inhibit Beclin1-Bcl2/xL interaction that is enhanced by phosphorylation of Beclin1. As a result, we could identified such a compound. According to in vivo experiments, that compound could effectively alleviates cardiac disfunction in transverse aortic constriction mouse models.

Research Products

• [Journal Article] Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress. (2017)
  • Author(s): Wakayama K, Shimamura M, Suzuki JI, Watanabe R, Koriyama H, Akazawa H, Nakagami H, Mochizuki H, Isobe M, Morishita R.
  • Journal Title: Stroke Volume: 48 Issue: 5 Pages: 1362-1368
  • DOI: 10.1161/strokeaha.116.016269
  • Peer Reviewed
• [Journal Article] A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction. (2017)
  • Author(s): Watanabe R, Suzuki JI, Wakayama K, Maejima Y, Shimamura M, Koriyama H, Nakagami H, Kumagai H, Ikeda Y, Akazawa H, Morishita R, Komuro I, Isobe M.
  • Journal Title: Sci Rep Volume: 7 Pages: 43920-43920
  • Peer Reviewed
• [Journal Article] A Periodontal pathogen Porphyromonas gingivalis deteriorates Isoproterenol-Induced myocardial remodeling in mice. (2017)
  • Author(s): Sato H, Suzuki JI, Aoyama N, Watanabe R, Kaneko M, Shiheido Y, Yoshida A, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M, Izumi Y.
  • Journal Title: Hypertens Res Volume: 40 Issue: 2 Pages: 35-40
  • DOI: 10.1038/hr.2016.117
  • Peer Reviewed
• [Journal Article] A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction. (2017)
  • Author(s): Watanabe R, Suzuki JI, Wakayama K, Maejima Y, Shimamura M, Koriyama H, Nakagami H, Kumagai H, Ikeda Y, Akazawa H, Morishita R, Komuro I, Isobe M.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 43920-43920
  • DOI: 10.1038/srep43920
  • Peer Reviewed / Open Access
• [Journal Article] Projections from single NUCB2/nesfatin-1 neuron in paraventricular nucleus to different brain regions involved in feeding (2016)
  • Author(s): Maejima Y, Kumamoto K, Takenoshita S, Shimomura K
  • Journal Title: Ｂｒａｉｎ Ｓｔｒｕｃｔｕｒｅ ａｎｄ Ｆｕｎｃｔｉｏｎ Volume: ｉｎ ｐｒｅｓｓ Pages: 123-137
  • DOI: 10.1016/j.yjmcc.2016.03.017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of autophagy by Beclin 1 in the heart. (2016)
  • Author(s): Maejima Y, Isobe M, Sadoshima J.
  • Journal Title: J Mol Cell Cardiol Volume: 95 Pages: 19-25
  • DOI: 10.1016/j.yjmcc.2015.10.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Influence of periostin-positive cell-specific Klf5 deletion on aortic thickening in DOCA-salt hypertensive mice. (2016)
  • Author(s): Zempo H, Suzuki JI, Ogawa M, Watanabe R, Fujiu K, Manabe I, Conway SJ, Taniyama Y, Morishita R, Hirata Y, Isobe M, Nagai R.
  • Journal Title: Hypertens Res Volume: 39 Issue: 11 Pages: 764-768
  • DOI: 10.1038/hr.2016.65
  • Peer Reviewed / Open Access
• [Journal Article] Toll-like receptor 4 signaling has a critical role in Porphyromonas gingivalis-accelerated neointimal formation after arterial injury in mice. (2016)
  • Author(s): Kobayashi N, Suzuki JI, Aoyama N, Sato H, Akimoto S, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Izumi Y, Isobe M.
  • Journal Title: Hypertens Res Volume: 39 Issue: 10 Pages: 717-722
  • DOI: 10.1038/hr.2016.58
  • Peer Reviewed
• [Journal Article] Cacao polyphenols ameliorate autoimmune myocarditis in mice (2016)
  • Author(s): Zempo H, Suzuki J, Watanabe R, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M
  • Journal Title: Hypertens Res Volume: 39 Issue: 4 Pages: 203-209
  • DOI: 10.1038/hr.2015.136
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiotensin II receptor blocker irbesartan attenuates cardiac dysfunction induced by myocardial infarction in the presence of renal failure (2016)
  • Author(s): Watanabe R, Suzuki J, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Isobe M
  • Journal Title: Hypertens Res Volume: 39 Issue: 4 Pages: 237-244
  • DOI: 10.1038/hr.2015.141
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: 10.1016/j.yjmcc.2015.11.034
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Suppression of murine autoimmune myocarditis achieved with direct renin inhibition. (2016)
  • Author(s): Takamura C, Suzuki J, Ogawa M, Watanabe R, Tada Y, Maejima Y, Akazawa H, Komuro I, Isobe M.
  • Journal Title: J Cardiol Volume: 68 Issue: 3 Pages: 253-60
  • DOI: 10.1016/j.jjcc.2015.09.008
  • Peer Reviewed
• [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, Furukawa T.
  • Journal Title: European Heart Journal. Volume: 37 (18) Issue: 18 Pages: 1469-1475
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A different role of angiotensin II type 1a receptor in the development and hypertrophy of plantaris muscle in mice (2016)
  • Author(s): Zempo H, Suzuki J, Ogawa M, Watanabe R, Isobe M.
  • Journal Title: J Appl Genet Volume: 57 Issue: 1 Pages: 91-7
  • DOI: 10.1007/s13353-015-0291-8
  • Peer Reviewed
• [Journal Article] A novel susceptibility locus for Takayasu arteritis in the IL12B region can be a genetic marker of disease severity. (2016)
  • Author(s): Matsumura T, Amiya E, Tamura N, Maejima Y, Komuro I, Isobe M.
  • Journal Title: Heart Vessels. Volume: 31 Issue: 6 Pages: 1016-9
  • DOI: 10.1007/s00380-015-0661-5
  • Peer Reviewed
• [Presentation] The Critical Role of Autophagy in the Progression of Heart Failure. (2017)
  • Author(s): 前嶋康浩
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)
  • Invited
• [Presentation] オートファジーの制御異常による心不全発症機構の解明 (2017)
  • Author(s): 前嶋康浩
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール(長崎県長崎市)
  • Invited
• [Presentation] The critical role of autophagy in the progression of heart failure (2017)
  • Author(s): 前嶋康浩
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Invited
• [Presentation] オートファジーの制御異常による心不全発症機構の解明 (2017)
  • Author(s): 前嶋康浩
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Invited
• [Presentation] 炎症を基盤とした拡張型心筋症に対するリナグリプチンの発症および病状進展抑制効果に関する機序についての研究 (2016)
  • Author(s): 前嶋康浩, 磯部光章
  • Organizer: 第20回日本適応医学会学術集会
  • Place of Presentation: 東京コンベンションホール(東京都中央区)
• [Presentation] GSK-3β inhibits cardiac hypertrophy by phosphorylating FoxO1 (2016)
  • Author(s): Yasuhiro Maejima, Narayani Nagarajan, Peiyong Zhai, Mitsuaki Isobe, Junichi Sadoshima.
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: Ernest N. Morial Convention Center(New Orleans, LA, USA)
  • Int'l Joint Research
• [Presentation] Junichi Sadoshima. GSK3β alleviates cardiac hypertrophy and LV dysfunction through modulation of FoxO1 activity in response to pressure overload (2016)
  • Author(s): Yasuhiro Maejima, Mitsuaki Isobe
  • Organizer: 第20回日本心不全学会学術集会
  • Place of Presentation: ロイトン札幌(北海道札幌市)
• [Presentation] Critical role for dipeptidyl peptidase-4 activity the pathogenesis of experimental autoimmune myocarditis (2016)
  • Author(s): Yasuhiro Maejima, Yusuke Ito, Natsuko Tamura, Mitsuaki Isobe.
  • Organizer: Basic Cardiovascular Sciences 2016 Scientific Sessions of American Heart Association
  • Place of Presentation: Hyatt Regency Phoenix(Phoenix, Arizona, U.S.A.)
  • Int'l Joint Research
• [Presentation] 炎症を基盤とした拡張型心筋症に対するリナグリプチンの発症および病状進展抑制効果に関する機序についての研究 (2016)
  • Author(s): 前嶋康浩, 磯部光章
  • Organizer: 第20回日本適応医学会学術集会
  • Place of Presentation: 東京コンベンションホール（東京都中央区）
• [Presentation] GSK-3β inhibits cardiac hypertrophy by phosphorylating FoxO1. (2016)
  • Author(s): Yasuhiro Maejima, Narayani Nagarajan, Peiyong Zhai, Mitsuaki Isobe, Junichi Sadoshima.
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: Ernest N. Moral Convention Center (New Orleans, LA, USA)
  • Int'l Joint Research
• [Presentation] Critical role for dipeptidyl peptidase-4 activity the pathogenesis of experimental autoimmune myocarditis. (2016)
  • Author(s): Yasuhiro Maejima, Yusuke Ito, Natsuko Tamura, Mitsuaki Isobe.
  • Organizer: Basic Cardiovascular Sciences 2016 Scientific Sessions of American Heart Association
  • Place of Presentation: Hyatt Regency Phoenix (Phoenix, Arizona, USA)
  • Int'l Joint Research