title: Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation.
abstract: OBJECTIVE
  Intensive insulin therapy with tight glucose control is known to result in reduced morbidity and mortality in inflammation-related critical illness. Tumor necrosis factor (TNF)-alpha induction in myocardial infarction may trigger inflammation and have detrimental effects on cardiomyocytes. This study was designed to investigate whether insulin attenuates TNF-alpha induction in acute myocardial ischemia/reperfusion (MI/R) and the underlying signaling mechanisms.
  
  
  METHODS
  Randomized experimental study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Sprague-Dawley rats.
  
  
  METHODS
  Anesthetized rats were subjected to MI/R (30 mins/3 hrs) and were treated with saline, glucose-insulin-potassium, or glucose-potassium infusion (4 mL/kg/hr intravenously). In vitro study was performed on cultured cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R).
  
  
  RESULTS
  In vivo treatment with glucose-insulin-potassium, but not glucose-potassium, significantly attenuated inflammatory response as evidenced by decreased TNF-alpha induction and myocardial myeloperoxidase activity, with concurrent reduction in creatine kinase activity and myocardial infarction compared with those in control rats. In cultured cardiomyocytes subjected to SI/R, insulin reduced TNF-alpha induction and increased Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and subsequent nitric oxide (NO) production. Inhibition of insulin-stimulated NO production using either the PI3K inhibitor wortmannin or the NOS inhibitor L-NAME blocked TNF-alpha reduction afforded by insulin. Furthermore, the suppression on TNF-alpha by either insulin or TNF-alpha neutralizing antibody improved viability and reduced apoptosis of cardiomyocytes subjected to SI/R.
  
  
  CONCLUSIONS
  Our data showed that insulin inhibits ischemia/reperfusion-induced TNF-alpha production through the Akt-activated and eNOS-NO-dependent pathway in cardiomyocytes. The anti-inflammatory property elicited by insulin may contribute to its cardioprotective and prosurvival effects in the critically ill.
authors.affiliation: Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Nan
authors.forename: Heng
authors.initials: H
authors.lastname: Ma
authors.forename: Wenyi
authors.initials: W
authors.lastname: Guo
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Undurti N
authors.initials: UN
authors.lastname: Das
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D000818:Animals; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt