title: Propofol ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction via heme oxygenase-1/signal transducer and activator of transcription 3 signaling pathway in rats.
abstract: OBJECTIVE
  Heme oxygenase-1 is inducible in cardiomyocytes in response to stimuli such as oxidative stress and plays critical roles in combating cardiac hypertrophy and injury. Signal transducer and activator of transcription 3 plays a pivotal role in heme oxygenase-1-mediated protection against liver and lung injuries under oxidative stress. We hypothesized that propofol, an anesthetic with antioxidant capacity, may attenuate hyperglycemia-induced oxidative stress in cardiomyocytes via enhancing heme oxygenase-1 activation and ameliorate hyperglycemia-induced cardiac hypertrophy and apoptosis via heme oxygenase-1/signal transducer and activator of transcription 3 signaling and improve cardiac function in diabetes.
  
  
  METHODS
  Treatment study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Sprague-Dawley rats.
  
  
  METHODS
  In vivo and in vitro treatments.
  
  
  RESULTS
  At 8 weeks of streptozotocin-induced type 1 diabetes in rats, myocardial 15-F2t-isoprostane was significantly increased, accompanied by cardiomyocyte hypertrophy and apoptosis and impaired left ventricular function that was coincident with reduced heme oxygenase-1 activity and signal transducer and activator of transcription 3 activation despite an increase in heme oxygenase-1 protein expression as compared to control. Propofol infusion (900 μg/kg/min) for 45 minutes significantly improved cardiac function with concomitantly enhanced heme oxygenase-1 activity and signal transducer and activator of transcription activation. Similar to the changes seen in diabetic rat hearts, high glucose (25 mmol/L) exposure for 48 hours led to cardiomyocyte hypertrophy and apoptosis, both in primary cultured neonatal rat cardiomyocytes and in H9c2 cells compared to normal glucose (5.5 mmol/L). Hypertrophy was accompanied by increased reactive oxygen species and malondialdehyde production and caspase-3 activity. Propofol, similar to the heme oxygenase-1 inducer cobalt protoporphyrin, significantly increased cardiomyocyte heme oxygenase-1 and p-signal transducer and activator of transcription protein expression and heme oxygenase-1 activity and attenuated high-glucose-mediated cardiomyocyte hypertrophy and apoptosis and reduced reactive oxygen species and malondialdehyde production (p < 0.05). These protective effects of propofol were abolished by heme oxygenase-1 inhibition with zinc protoporphyrin and by heme oxygenase-1 or signal transducer and activator of transcription 3 gene knockdown.
  
  
  CONCLUSIONS
  Heme oxygenase-1/signal transducer and activator of transcription 3 signaling plays a critical role in propofol-mediated amelioration of hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis, whereby propofol improves cardiac function in diabetic rats.
authors.affiliation: 1Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China. 2Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. 3Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 4Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. 5Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.forename: Haobo
authors.initials: H
authors.lastname: Li
authors.forename: Michael G
authors.initials: MG
authors.lastname: Irwin
authors.forename: Zhong-Yuan
authors.initials: ZY
authors.lastname: Xia
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Mao
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Lei
authors.forename: Gordon T
authors.initials: GT
authors.lastname: Wong
authors.forename: Victor
authors.initials: V
authors.lastname: Hung
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Cheung
authors.forename: Xiangming
authors.initials: X
authors.lastname: Fang
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D051700:Activating Transcription Factor 3 / Q000187:drug effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications*; D004789:Enzyme Activation; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051700:Activating Transcription Factor 3; D000975:Antioxidants; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D015742:Propofol