title: Heat shock protein 70 and AMP-activated protein kinase contribute to 17-DMAG-dependent protection against heat stroke.
abstract: Heat shock protein 70 (Hsp70) preconditioning induces thermotolerance, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a role in the process of autophagy. Here, we investigated whether 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) protected against heat stroke (HS) in rats by up-regulation of Hsp70 and phosphorylated AMPK (pAMPK). To produce HS, male Sprague-Dawley rats were placed in a chamber with an ambient temperature of 42°C. Physiological function (mean arterial pressure, heart rate and core temperature), hepatic and intestinal injury, inflammatory mediators and levels of Hsp70, pAMPK and light chain 3 (LC3B) in hepatic tissue were measured in HS rats or/and rats pre-treated with 17-DMAG. 17-DMAG pre-treatment significantly attenuated hypotension and organ dysfunction induced by HS in rats. The survival time during HS was also prolonged by 17-DMAG treatment. Hsp70 expression was increased, whereas pAMPK levels in the liver were significantly decreased in HS rats. Following pre-treatment with 17-DMAG, Hsp70 protein levels increased further, and pAMPK levels were enhanced. Treatment with an AMPK activator significantly increased the LC3BII/LC3BI ratio as a marker of autophagy in HS rats. Treatment with quercetin significantly suppressed Hsp70 and pAMPK levels and reduced the protective effects of 17-DMAG in HS rats. Both of Hsp70 and AMPK are involved in the 17-DMAG-mediated protection against HS. 17-DMAG may be a promising candidate drug in the clinical setting.
authors.affiliation: Department of Obstetrics and Gynecology, Chi-Mei Medical Center, Tainan, Taiwan.|Department of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Sport Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Yung-Chieh
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.|Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu, Taiwan.
authors.forename: Kwok-Keung
authors.initials: KK
authors.lastname: Lam
authors.affiliation: Department of Pathology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yen-Mei
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Tsai
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Mao-Hsiung
authors.initials: MH
authors.lastname: Yen
authors.affiliation: Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan. pycheng@mail.ndmctsgh.edu.tw.
authors.forename: Pao-Yun
authors.initials: PY
authors.lastname: Cheng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D018883:Heat Stroke / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D018836:Inflammation Mediators; D047029:Lactams, Macrocyclic; D020011:Protective Agents; D014157:Transcription Factors; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D055372:AMP-Activated Protein Kinases
keywords: 17-DMAG; AMP-activated protein kinase; autophagy; heat shock protein 70; heat stroke; mortality