2005 Fiscal Year Final Research Report Summary
Control of cardiovascular diseases in animal model of obese/type2 diabetes by heat-shock protein 72 through anti-TNF-alpha effects.
| Project/Area Number |
16590699
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Oita University |
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Principal Investigator |
TAKAHASHI Naohiko Oita University, Faculty of Medicine, Internal Medicine, Assistant professor, 医学部, 助手 (30263239)
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| Project Period (FY) |
2004 – 2005
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| Keywords | heat-shock protein / ischemia / reperfusion injury / PI3 kinase / OLETF rat / pioglitazone |
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| Research Abstract |
We tested the hypothesis that phosphatidylinositol 3-kinase (PI 3-kinase)-dependent activation of Akt is essential for the expression of cardiac heat-shock protein 72 (HSP72) and that this pathway is impaired in the streptozotocin (STZ)-induced diabetic heart. STZ-induced male diabetic rats were treated with insulin (STZ-insulin group, n=26) or vehicle (STZ-vehicle group, n=61) for 3 weeks. Whole-body hyperthermia (43 degrees C for 20 min) was applied, and the heart was isolated 24 h later. Compared with control heart, hyperthermia-induced HSP72 expression and phosphorylation of Akt were attenuated in the STZ-vehicle heart. Pretreatment with wortmannin attenuated hyperthermia-induced HSP72 expression and phosphorylation of Akt. In isolated perfused heart experiments, the hyperthermia-treated STZ-vehicle heart showed poor left ventricular functional recovery during reperfusion after no-flow global ischemia compared with hyperthermia-treated control heart. Insulin treatment restored HSP7
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2 expression and reperfusion-induced functional recovery. In cultured neonatal rat cardiomyocytes, hyperthermia-induced HSP72 expression was enhanced by insulin, together with tolerance against hypoxia-reoxygenation injury. Wortmannin and LY294002 inhibited hyperthermia-induced HSP72 expression and phosphorylation of Akt. Our results indicate that activation of Akt, in a PI 3-kinase-dependent manner, is essential for hyperthermia-induced HSP72 expression in association with cardioprotection, suggesting impairment of this signaling pathway in the STZ-induced diabetic heart, probably due to insulin deficiency (Diabetes, 2006).
We tested the hypothesis that pioglitazone could restore expression of HSP72 in insulin-resistant rat heart. At 12 weeks of age, male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control (LETO) rats were treated with pioglitazone (10 mg/kg/day), glibenclamide (5 mg/kg/day) for 4 weeks. Thereafter, hyperthermia (HT ; 43℃ for 20 min) was applied. In response to HT, the activation of serine/threonine kinase Akt depending on phosphatidylinositol 3 (PI3) kinase was necessary for cardiac expression of HSP72. HT-induced activation of Akt and HSP72 expression were depressed in OLETF rat hearts. Pioglitazone but not glibenclamide improved insulin sensitivity in OLETF rats, which was associated with the restoration of Akt activation and HSP72 expression. In experiments with isolated perfused heart, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by pioglitazone but not glibenclamide. Our results suggest that PI3 kinase-dependent Akt activation, an essential signal for HSP72 expression, is depressed in the heart in insulin-resistant OLETF rats, and the results suggest also that the restoration of HSP72 expression and tolerance against ischemia/reperfusion injury by treatment with pioglitazone might be due to an improvement of insulin resistance, leading to restoration of impaired PI3 kinase-dependent Akt activation in response to HT (Diabetes, in press). Less
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Research Products
(7 results)
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[Journal Article] Phosphatidylinositol 3 kinase-dependent activation of Akt,an essential signal for hyperthermia-induced heat shock protein 72,is attenuated in streptozotocin-induced diabetic heart2006
Author(s)
Shinohara T, Takahashi N, Ooie T, Hara M, Shigematsu S, Nakagawa M, Yonemochi H, Saikawa T, Yoshimatsu H.
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Journal Title
Diabetes 55
Pages: 1307-1315
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Phosphatidylinositol 3 kinase-dependent activation of Akt, an essential signal for hyperthermia-induced heat shock protein 72, is attenuated in streptozotocin-induced diabetic heart.2006
Author(s)
Shinohara T, Takahashi N, Ooie T, Hara M, Shigematsu S, Nakagawa M, Yonemochi H, Saikawa T, Yoshimatsu H.
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Journal Title
Diabetes 55
Pages: 1307-1315
Description
「研究成果報告書概要(欧文)」より
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