Phosphatidylinositol 3-kinase-dependent activation of akt, an essential signal for hyperthermia-induced heat-shock protein 72, is attenuated in streptozotocin-induced diabetic heart.
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 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.
Shinohara
Tetsuji
T
Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
Takahashi
Naohiko
N
Ooie
Tatsuhiko
T
Hara
Masahide
M
Shigematsu
Sakuji
S
Nakagawa
Mikiko
M
Yonemochi
Hidetoshi
H
Saikawa
Tetsunori
T
Yoshimatsu
Hironobu
H
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005334:Fever; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D009929:Organ Size; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D000077191:Wortmannin
D000730:Androstadienes; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D050884:HSP72 Heat-Shock Proteins; D007328:Insulin; D014280:Triglycerides; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin