Mechanism of myocardial apoptosis induced by high glucose

• Project/Area Number: 17590754
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Oita University
• Principal Investigator: YONEMOCHI Hidetoshi Oita University, Department of Cardiovascular Science, Associated Professor (40191671)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Naohiko Oita University, Department of Internal Medicine I, Research Associate (30263239)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,710,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: apoptosis / reactive oxygen species / mitochondria / hyperglycemia / heat shock protein / グルタチオン

Research Abstract

Diabetes and hyperglycemia are clear contributors to poor prognosis and the high incidence of cardiovascular diseases including heart failure, and these complications have become the major cause of morbidity and mortality in the diabetic population. Recent studies reported that the incidence of apoptosis increases in the hearts of patients with diabetes. However, the precise role and the cellular mechanism of apoptosis or decreased ischemic tolerance in diabetes are not clear. We investigated roles of hyperglycemia-induced reactive oxygen species (ROS) production and expression of heat shock protein 72 in decreased ischemic tolerance in vitro cultured cell model and diabetic animal model. Hyperglycemia exhibited dual effects on cultured neonatal rat myocardial survival, either inhibiting or promoting apoptosis. Compared with normal glucose, in high glucose condition the rate of apoptotic cell decreased within 72h, but inversely increased at 120h. Exposure to H_2O_2 increased apoptosis in high glucose condition both at 72 and 120h, and decreased intracellular glutathione content. Normalization of the ROS production by their scavengers or agents that alter mitochondrial metabolism abolished the observed the anti-apoptotic effect and the increased susceptibility. Next, we investigated the expression of HSP 72 and tolerance against ischemia/reperfusion injury. In STZ-induced diabetic model, hyperthermia-induced HSP expression and phosphorylation of Akt were attenuated. Also, reperfusion-induced functional recovery was attenuated. Observed disorders were restored by insulin treatment. In cultured cardiomyocytes, hyperthermia-induced HSP72 expression was enhanced by insulin and attenuated by wartomanin. Our results indicate possible two mechanisms responsible for decreased tolerance to ischemia/reperfusion injury in diabetic hearts. One of them is hyperglycemia-induced ROS production in mitochondria. The other is impairment of PI3-kinase/Akt signaling pathway and HSP expression.

Research Products

• [Journal Article] Phosphatidilinositol 3 kinase-dependent activation of Akt,an essential signal for hyperthermia-induced heart shock protein 72,is attenuated in streptozocin-induced diabetic heart (2006)
  • Author(s): Shinohara T, Takahashi N, Ooie T, Hara M, Shigematsu S, Nakagawa M, Yonemochi H, Saikawa T, Yoshimatsu H
  • Journal Title: Diabetes 55 Pages: 1307-1315
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pioglitazone but not Glibenclamide Improves Cardiac Expression of Heat-Shock Protein 72 and Tolerance against Ischemia/Reperfusion Injury in the Heredity Insulin-Resistant Rat (2006)
  • Author(s): Taniguchil Y., Ooiel T., Takahashi N., Shinohara T., Nakagawa M., Yonemochi H., Hara M., Yoshimatsu H., Saikawa T
  • Journal Title: Diabetes 55 Pages: 2371-2378
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Diazoxide-induced cardioprotection via ΔΨm loss depending on timing of application (2006)
  • Author(s): Yonemochi H., Ichinose M., Aran F., Taniguti Y., Shinohara T., Takahashi N., Nakagawa M., Saikawa T
  • Journal Title: Life. Sci. 79 Pages: 1906-1912
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Phosphatidilinositol 3 kinase-dependent activation of Akt, an essential signal for hyperthermia-induced heart shock protein 72, is attenuated in streptozocin-induced diabetic heart (2006)
  • Author(s): Shinohara, T., Takahashi, N., Ooie, T., Hara, M., Shigematsu, S., Nakagawa, M., Yonemochi, H., Saikawa, T., Yoshimatsu, H.
  • Journal Title: Diabetes 55 Pages: 1307-1315
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Heat-Shock Protein 72 and Tolerance against Ischemia/Reperfusion Injury in the Heredity Insulin-Resistant Rat (2006)
  • Author(s): Taniguchil, Y., Ooiel, T., Takahashi, N., Shinohara, T., Nakagawa, M., Yonemochi, H., Hara, M., Yoshimatsu, H., Saikawa, T.
  • Journal Title: Diabetes 55 Pages: 2371-2378
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Diazoxide-induced cardioprotection via ΔΨm loss depending on timing of application (2006)
  • Author(s): Yonemochi, H., Ichinose, M., Anan, F., Taniguti, Y., Shinohara, T., Takahashi, N., Nakagawa, M., Saikawa, T.
  • Journal Title: Life. Sci. 79 Pages: 1906-1912
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Diazoxide-induced cardioprotection via ΔΨm loss depending on timing of application. (2006)
  • Author(s): Yonemochi H.
  • Journal Title: Life.Sci. 79 Pages: 1906-1912
• [Journal Article] Phosphatidilinositol 3 kinase-dependent activation of Akt, an essential signal for hyperthermia-induced heart shock protein 72, is attenuated in streptozocin-induced diabetic heart. (2006)
  • Author(s): Shinohara T
  • Journal Title: Diabetes 55 Pages: 1307-1315
• [Presentation] Role of mitochondrial ROS production associated with glucose metabolism in development of diabetic cardiomyopathy (2007)
  • Author(s): Yonemochi, H, Ichinose M, Saikawa T
  • Organizer: 第71回日本循環器学会総会・学術集会シンポジウム
  • Place of Presentation: 神戸
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Candesaltan improves cardiac expression of HSP72 and tolerance against ischemia/reperfusion injury in heredity insulin-resistance rat (2007)
  • Author(s): Taniguchi Y, Ooie T, Takahashi N, Shinohara T, Torigoe T, Yufu K, Nakagawa M, Yonemochi H, Yoshimatsu H, Saikawa T
  • Organizer: 第71回日本循環器学会総会・学術集会
  • Place of Presentation: 神戸
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of mitochondrial ROS production associated with glucose metabolism in development of diabetic cardiomyopathy (2007)
  • Author(s): Yonemochi, H., Ichinose, M., Saikawa, T.
  • Organizer: The 71th Annual scientific meeting of JCS.
  • Place of Presentation: Kobe
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Candesartan improves cardiac expression of HSP72 and tolerance against ischemia/reperfusion injury in heredity insulin-resistance rat (2007)
  • Author(s): Taniguchi, Y., Ooie, T., Takahashi, N., Shinohara, T., Torigoe, T., Yufu, K., Nakagawa, M., Yonemochi, H., Yoshimatsu, H., Saikawa, T.
  • Organizer: The 71th Annual scientific meeting of JCS.
  • Place of Presentation: Kobe
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Insulin deficiency potentiates geranylgeranylacetone-induced heat shock protein 72 in association with protection against ischemia/reperfusion in rat heart (2006)
  • Author(s): Shinohara T, Takahashi N, Ooie T, Taniguchi Y, Murozono Y, Wakisaka O, Kohno H, Hara M, Yoshimatsu H, Saikawa T
  • Organizer: 第70回日本循環器学会総会・学術集会
  • Place of Presentation: 名古屋
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Insulin deficiency potentiates geranylgeranylacetone-induced heat shock protein 72 in association with protection against ischemia/reperfusion in rat heart (2006)
  • Author(s): Shinohara, T., Takahashi, N., Ooie, T., Taniguchi, Y., Murozono, Y., Wakisaka, O., Kohno, H., Hara, M., Yoshimatsu, H., Saikawa, T.
  • Organizer: The 70th Annual scientific meeting of JCS.
  • Place of Presentation: Nagoya
  • Description: 「研究成果報告書概要(欧文)」より