title: Candesartan restored cardiac Hsp72 expression and tolerance against reperfusion injury in hereditary insulin-resistant rats.
abstract: OBJECTIVE
  We tested the hypothesis that candesartan, an angiotensin II (AII) type 1 receptor antagonist, would restore the depressed phosphatidylinositol 3 (PI3) kinase-dependent Akt phosphorylation, an essential signal to induce heat-shock protein 72 (Hsp72) in response to hyperthermia, in Otsuka Long-Evans Tokushima fatty (OLETF) rats.
  
  
  RESULTS
  At 14 weeks of age, male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats were treated with candesartan (0.25 mg/kg/day) for 2 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. We observed the following: (i) Candesartan did not improve insulin sensitivity in OLETF rats. (ii) Candesartan restored depressed PI3 kinase-dependent Akt phosphorylation and Hsp72 expression in OLETF rat hearts. (iii) Cardiac ventricular tissue contents of AII were greater in OLETF rats, which were suppressed by candesartan. (iv) Cardiac levels of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation were greater in OLETF rats, which were suppressed by candesartan. In cultured cardiomyocytes, application of AII induced PTEN phosphorylation, which was suppressed by candesartan. (v) In high-fat diet insulin-resistant rats, similar results were observed with respect to Hsp72 expression, Akt phosphorylation and PTEN phosphorylation. (vi) In isolated, perfused heart experiments, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by candesartan.
  
  
  CONCLUSIONS
  Our results suggest that the depression of PI3 kinase-dependent Akt activation in response to hyperthermia in OLETF rats can be restored by candesartan. Substantial activation of the renin-angiotensin system, represented by increased myocardial AII content and subsequent PTEN phosphorylation, may underlie the pathogenesis which is ameliorated by candesartan.
authors.affiliation: Department of Laboratory Examination and Diagnostics,  Faculty of Medicine, Oita University, 1-1 Idaigaoka, Yufu, Oita 879-5593,  Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Naohiko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Akira
authors.initials: A
authors.lastname: Fukui
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nagano-Torigoe
authors.forename: Luong Cong
authors.initials: LC
authors.lastname: Thuc
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Teshima
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Shinohara
authors.forename: Osamu
authors.initials: O
authors.lastname: Wakisaka
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ooie
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Murozono
authors.forename: Kunio
authors.initials: K
authors.lastname: Yufu
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Masahide
authors.initials: M
authors.lastname: Hara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yoshimatsu
authors.forename: Tetsunori
authors.initials: T
authors.lastname: Saikawa
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D040941:Heredity; D006979:Hyperthermia, Induced; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D020127:Recovery of Function; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D050884:HSP72 Heat-Shock Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C495694:Slc2a4 protein, rat; D013777:Tetrazoles; D000804:Angiotensin II; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; C081643:candesartan