| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
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 (10mg/kg/day), glibenclamide (5 mg/kg/day) for 4 weeks. Thereafter, hyperthermia (HT; 43°C 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 act
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ivation, 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, 2006).
The impact of testosterone on cardiac expression of HSP72 remains to be elucidated. Male Sprague-Dawley rats 10 weeks of age (adult) were castrated. Four weeks later, testosterone (10 mg/kg, i. p.) was administered as a single dose, followed by the application of hyperthermia (HT; 43°C) at 6 h after testosterone administration. Twenty-four hours later, each heart was isolated. Cardiomyocytes were prepared from 3-to 5-day-old Wistar rats and male Sprague-Dawley rats 10 weeks of age. Testosterone (0.1-10 μM) was added to the medium followed by the application of HT (42°C). Twenty-four hours later, cells were collected. We observed the following: 1) Exogenous testosterone suppressed HT-induced HSP72 expression but castration alone had no influence. 2) HT resulted in better reperfusion-induced cardiac performance in castrated rats comparable to sham-operatic rats, which was inhibited by testosterone. The number of apoptotic cells following ischemia/reperfusion was also increased by testosterone. 3) HT-induced HSP72 expression in cultured cardiomyocytes was suppressed by testosterone. 4) HT resulted in less damage to cells, including apoptosis, in response to hypoxia/reoxygenation, which was inhibited by testosterone. 5) Flutamide, a testosterone receptor blocker, cancelled the suppressive effects of testosterone on HSP72 expression. 6) The HT-induced increase in heat-shock factor 1 activity to bind to heat-shock element DNA was suppressed by testosterone, and this was reversed by flutamide. Our results indicate that testosterone potentially has inhibitory effects on cardiac HSP72 expression by modulating transcription, through testosterone receptor-mediated genomic mechanisms (Endocrinology, 2007). Less
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