Role of cardiac insulin resistance on left ventricular diastolic dysfunction in diabetes cardiomyopathy

• Project/Area Number: 16K09428
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: SAOTOME MASAO 浜松医科大学, 医学部附属病院, 助教 (70509512)
• Co-Investigator(Kenkyū-buntansha): 佐藤 洋 浜松医科大学, 医学部附属病院, 講師 (30293632) ; 林 秀晴 浜松医科大学, 医学部, 教授 (50135258) ; 加藤 秀樹 浜松医科大学, 医学部, 助教 (80314029)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 左室拡張障害 / ミトコンドリア / 糖尿病 / インスリン抵抗性 / ミトコンドリア形態異常 / 虚血耐性 / 心筋代謝 / 心筋インスリン抵抗性 / 拡張障害 / 糖尿病性心筋症

Outline of Final Research Achievements

In this project, we first aimed to investigate the relationship between left ventricular diastolic dysfunction and cardiac insulin resistance using diabetic rats. However, because we did not obtain clear diastolic disfunction in the diabetic rat, we changed our focus on hypertensive rat model (Dahl rat), instead of DM. When we fed the Dahl rats with high-salt diet, they showed hypertension, hypertensive-left ventricular hypertrophy, cardiac fibrosis, and left ventricular diastolic dysfunction. In addition, the hypertrophied myocardium revealed the increased Drp1 (a mitochondrial fission protein) expression. Furthermore, application of mdivi1, an inhibitor of Drp1,to Dahl rats attenuated the hypertension-induced left-ventricular hypertrophy and cardiac fibrosis, without altering blood pressure.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、ミトコンドリア分裂タンパクであるDrp1が高血圧誘発性の左室肥大および心筋線維化の病態形成に重要な役割を果たしていることが明らかになった。またDrp1の抑制剤であるmdivi1投与は高血圧による左室肥大と心筋線維化を抑制しており、Drp1は高血圧性心機能障害の治療ターゲットとなり、左室拡張障害に対しても効果を示す可能性があることが示唆された。さらなる研究を行うことにより、わが国の高血圧性心機能障害および拡張障害を有する患者に対して有用な治療手段を届けることができる可能性もあると考えられた。

Research Products

• [Journal Article] Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats. (2018)
  • Author(s): Hasan P, Saotome M, Ikoma T, Iguchi K, Kawasaki H, Iwashita T, Hayashi H, Maekawa Y.
  • Journal Title: J Mol Cell Cardiol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Glycogen synthase kinase-3β opens mitochondrial permeability transition pore through mitochondrial hexokinase II dissociation (2018)
  • Author(s): Tanaka Takamitsu、Saotome Masao、Katoh Hideki、Satoh Terumori、Hasan Prottoy、Ohtani Hayato、Satoh Hiroshi、Hayashi Hideharu、Maekawa Yuichiro
  • Journal Title: The Journal of Physiological Sciences Volume: 68 Issue: 6 Pages: 865-871
  • DOI: 10.1007/s12576-018-0611-y
  • Peer Reviewed
• [Journal Article] ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak (2017)
  • Author(s): Debattisti Valentina、Gerencser Akos A.、Saotome Masao、Das Sudipto、Hajnoczky Gyorgy
  • Journal Title: Cell Reports Volume: 21 Issue: 6 Pages: 1667-1680
  • DOI: 10.1016/j.celrep.2017.10.060
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intracellular Renin Inhibits Mitochondrial Permeability Transition Pore via Activated Mitochondrial Extracellular Signal-Regulated Kinase (ERK) 1/2 during Ischemia in Diabetic Hearts (2017)
  • Author(s): Satoh Terumori、Saotome Masao、Katoh Hideki、Nonaka Daishi、Hasan Prottoy、Hayashi Hideharu、Maekawa Yuichiro
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 1 Pages: 55-55
  • DOI: 10.3390/ijms19010055
  • Peer Reviewed
• [Journal Article] Eicosapentaenoic acid ameliorates palmitate-induced lipotoxicity via the AMP kinase/dynamin-related protein-1 signaling pathway in differentiated H9c2 myocytes. (2017)
  • Author(s): Sakamoto A, Saotome M, Hasan P, Satoh T, Ohtani H, Urushida T, Katoh H, Satoh H, Hayashi H
  • Journal Title: Exp Cell Res Volume: 351 Issue: 1 Pages: 109-120
  • DOI: 10.1016/j.yexcr.2017.01.004
  • Peer Reviewed
• [Journal Article] Aberrant serum polyunsaturated fatty acids profile is relevant with acute coronary syndrome. (2016)
  • Author(s): Sakamoto A, Saotome M, Hosoya N, Kageyama S, Yoshizaki T, Takeuchi R, Murata K, Nawada R, Onodera T, Takizawa A, Satoh H, Hayashi H.
  • Journal Title: Heart Vessels Volume: 31 Issue: 8 Pages: 1209-17
  • DOI: 10.1007/s00380-015-0721-x
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Dynamin-related protein1 (Drp1) contributes to cardiac hypertrophy in salt sensitive hypertensive Dahl rat via ROS production (2018)
  • Author(s): Prottoy Hasan, Masao Saotome,
  • Organizer: 第82回日本循環器学会総会
• [Presentation] Dose dependent effects of mitochondrial division inhibitor (mdivi-1) on hypertensive cardiac hypertrophy in salt sensitive Dahl rats (2018)
  • Author(s): Ikoma T, Saotome M,
  • Organizer: 第82回日本循環器学会総会
• [Presentation] Activated intracellular renin protects diabetic myocytes from ischemic injury via Extracellular Signal-regulated Kinase (ERK) activation (2018)
  • Author(s): Terumori Satoh, Hideki Katoh, Masao Saotome,
  • Organizer: 第一回日本循環器学会基礎研究フォーラム
• [Presentation] Eicosapentaenoic acid ameliorates palmitate-induced lipotoxicity via the AMP kinase/dynamin-related protein-1 signaling pathway. (2017)
  • Author(s): Sakamoto A, Saotome M, Prottoy H, Satoh T, Ohtani H, Urushida T, Katoh H, Satoh H, and Hayashi H
  • Organizer: The 81th Annual Meeting of Japanese Circulation Society
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Dynamin related protein 1 contributes cardiac hypertrophy in salt sensitive Dahl rat. (2017)
  • Author(s): Prottoy H, Saotome M, Sakamoto A, Satoh T, Ohtani H, Urushida T, Katoh H, Satoh H, and Hayashi H
  • Organizer: The 81th Annual Meeting of Japanese Circulation Society
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Activation of mitochondrial ERK1/2 is involved in an intracellular renin mediated ischemic resistance in diabetic hearts. (2017)
  • Author(s): Satoh T, Katoh H, Saotome M, Nonaka D, Sakamoto A, Prottoy H, Satoh H, and Hayashi H
  • Organizer: The 81th Annual Meeting of Japanese Circulation Society
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Dynamin-related protein1 (Drp1) contributes to cardiac hypertrophy in salt sensitive Dahl rat. (2017)
  • Author(s): Hasan P, Saotome M, Ikoma T, Iguchi K, Sato T, Sakamoto A, Maekawa Y
  • Organizer: he 21st Annual Scientific Meeting of the Japanese Heart Failure Society.
• [Presentation] Intracellular renin inhibits mitochondrial permeability transition pore via an activated mitochondrial ERK1/2 during ischemia in diabetic hearts. (2017)
  • Author(s): Satoh T, Katoh H, Saotome M, Nonaka D, Sakamoto A, Hasan P , Satoh H, Hayashi H, and Maekawa Y
  • Organizer: The 21st Annual Scientific Meeting of the Japanese Heart Failure Society.
• [Presentation] Intracellular renin inhibits mitochondrial permeability transition pore via an activated mitochondrial ERK1/2 during ischemia in diabetic hearts. (2017)
  • Author(s): Satoh T, Katoh H, Saotome M, Nonaka D, Sakamoto A, Hasan P, Satoh H, Hayashi H:
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] “Role Mitochondrial dynamics in cardiac disease” (2017)
  • Author(s): Saotome M, Maekawa Y
  • Organizer: Invited lecture in NICVD Bangladesh,
  • Int'l Joint Research / Invited
• [Presentation] エイコサペンタエン酸(EPA)はミトコンドリア分裂蛋白（DRP1）の発現抑制を介してパルミチン酸誘発性アポトーシスを制御する (2016)
  • Author(s): 早乙女雅夫、坂本篤志、Hasan Prottoy、佐藤照盛、大谷速人、漆田 毅、加藤秀樹、佐藤洋、林 秀晴
  • Organizer: 第20回日本適応医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-16