Phosphatidylinositol 3-Kinase–Dependent Activation of Akt, an Essential Signal for Hyperthermia-Induced Heat-Shock Protein 72, Is Attenuated in Streptozotocin-Induced Diabetic Heart
- Tetsuji Shinohara1,
- Naohiko Takahashi1,
- Tatsuhiko Ooie2,
- Masahide Hara1,
- Sakuji Shigematsu1,
- Mikiko Nakagawa2,
- Hidetoshi Yonemochi2,
- Tetsunori Saikawa2 and
- Hironobu Yoshimatsu1
- 1Department of Internal Medicine 1, Faculty of Medicine, Oita University, Oita, Japan
- 2Department of Laboratory Medicine, Faculty of Medicine, Oita University, Oita, Japan
- Address correspondence and reprint requests to Naohiko Takahashi, MD, PhD, Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail: takanao{at}med.oita-u.ac.jp
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°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 HSP72 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.
- CPP, coronary perfusion pressure
- DMEM, Dulbecco’s modified Eagle’s medium
- GSK, glycogen synthase kinase
- HSE, heat-shock element
- HSF1, heat-shock factor 1
- HSP72, heat-shock protein 72
- LDH, lactate dehydrogenase
- LV, left ventricle
- LVDP, LV developed pressure
- PI 3-kinase, phosphatidylinositol 3-kinase
- released CK, creatine kinase content
- siRNA, small interfering RNA
- STZ, streptozotocin
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted January 31, 2006.
- Received March 3, 2005.
- DIABETES
