Pioglitazone but Not Glibenclamide Improves Cardiac Expression of Heat Shock Protein 72 and Tolerance Against Ischemia/Reperfusion Injury in the Heredity Insulin-Resistant Rat
Pioglitazone but Not Glibenclamide Improves Cardiac Expression of Heat Shock Protein 72 and Tolerance Against Ischemia/Reperfusion Injury in the Heredity Insulin-Resistant Rat
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DOI：
10.2337/db06-0268
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发表时间：
2006-08
期刊：
影响因子：
7.7
通讯作者：
Yayoi Taniguchi;T. Ooie;N. Takahashi;T. Shinohara;M. Nakagawa;H. Yonemochi;M. Hara;H. Yoshimatsu;T. Saikawa
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作者：
Yayoi Taniguchi;T. Ooie;N. Takahashi;T. Shinohara;M. Nakagawa;H. Yonemochi;M. Hara;H. Yoshimatsu;T. Saikawa
我们验证了吡格列酮可以恢复胰岛素抵抗大鼠心脏热休克蛋白（HSP）72的表达的假设。在12周龄时，雄性大冢Long-Evans德岛脂肪（OLETF）大鼠和对照（LETO）大鼠接受吡格列酮（10 mg·kg − 1·d − 1）或格列本脲（5 mg·kg − 1·d − 1）治疗4周。此后，施加热疗（43 ° C持续20分钟）。在高温反应中，依赖于磷脂酰肌醇3（PI3）激酶的丝氨酸/苏氨酸激酶Akt的激活是心脏表达HSP 72所必需的。在OLETF大鼠心脏中，高血压诱导的Akt活化和HSP72表达被抑制。吡格列酮而不是格列本脲改善OLETF大鼠的胰岛素敏感性，这与Akt激活和HSP72表达的恢复有关。在离体心脏灌注实验中，OLETF大鼠心脏再灌注诱导的心功能恢复受到抑制，吡格列酮可改善，而格列本脲则无此作用。我们的研究结果表明，PI3激酶依赖的Akt激活，HSP72表达的一个重要信号，在胰岛素抵抗的OLETF大鼠的心脏中被抑制，并且结果还表明，通过吡格列酮治疗，HSP72表达的恢复和对缺血/再灌注损伤的耐受性可能是由于胰岛素抵抗的改善，导致响应于高热的受损的PI3激酶依赖性Akt活化的恢复。
We tested the hypothesis that pioglitazone could restore expression of heat shock protein (HSP)72 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−1 · day−1) or glibenclamide (5 mg · kg−1 · day−1) for 4 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. In response to hyperthermia, the activation of serine/threonine kinase Akt depending on phosphatidylinositol 3 (PI3) kinase was necessary for cardiac expression of HSP72. Hyperthermia-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 hyperthermia.