title: Resveratrol alleviates endotoxin-induced myocardial toxicity via the Nrf2 transcription factor.
abstract: OBJECTIVE
  Septic cardiomyopathy is a severe condition that remains a challenge for clinical management. This study investigated whether the natural polyphenolic compound resveratrol could be used as a prophylactic treatment to alleviate sepsis-related myocardial injury; the underlying molecular mechanisms were deciphered by both in vitro and in vivo experiments.
  
  
  METHODS
  A mouse model of endotoxin-induced cardiomyopathy was developed by intraperitoneal injection of LPS, and resveratrol was administered prophylatically to the animals. Serum LDH and CK activities were measured to detect myocardial injury, and echocardiography was performed to monitor cardiac structure and function. Various cytokines/chemokines and the Nrf2 antioxidant defense system were examined in the heart tissue. The effects of resveratrol on LPS-induced Nrf2 activation, ROS generation, and apoptotic cell death were further investigated in cultured primary human cardiomyocytes. An Nrf2 specific siRNA was used to define its role in resveratrol-mediated cardiomyocyte protective effect.
  
  
  RESULTS
  Resveratrol pretreatment significantly attenuated LPS-induced myocardial injury in mice, which was associated with suppressed proinflammatory cytokine production and enhanced Nrf2 activation in the heart. In cultured primary human cardiomyocytes, resveratrol activated Nrf2, inhibited LPS-induced ROS generation, and effectively protected the cells from LPS-induced apoptotic cell death. Knockdown of Nrf2 abrogated resveratrol-mediated protection of the cells from LPS-induced cell death.
  
  
  CONCLUSIONS
  Resveratrol effectively alleviates endotoxin-induced cardiac toxicity through mechanisms that involve the Nrf2 antioxidant defense pathway. Our data suggest that resveratrol might be developed as a useful prophylactic management for septic cardiomyopathy.
authors.affiliation: Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, Jinan, China.
authors.forename: Enkui
authors.initials: E
authors.lastname: Hao
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lang
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Cong
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Shen
authors.forename: Guohai
authors.initials: G
authors.lastname: Su
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000077185:Resveratrol
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