title: The PI3K/Akt pathway mediates the nongenomic cardioprotective effects of estrogen following trauma-hemorrhage.
abstract: OBJECTIVE
  To determine whether the nongenomic actions of E2 have any beneficial effect on cardiac function following trauma-hemorrhage and whether those effects are mediated via the PI3K/Akt pathway.
  
  
  BACKGROUND
  Since studies suggest that both genomic and nongenomic pathways are involved in mediating the salutary effects of 17beta-estradiol (estradiol) following trauma-hemorrhage, we examined if the nongenomic effects of estradiol on cardiac function after trauma-hemorrhage involve the PI3K/Akt pathway.
  
  
  METHODS
  Male Sprague-Dawley rats ( approximately 300 g) underwent trauma-hemorrhage (mean blood pressure, 40 mm Hg for 90 min, then resuscitation). Estradiol conjugated to bovine serum albumin (BSA) (estradiol-BSA; 1 mg/kg estradiol) with or without estrogen receptor antagonist (ICI 182,780), PI3K inhibitor (Wortmannin), or vehicle was injected intravenously during resuscitation. At 2 hours after trauma-hemorrhage or sham operation, cardiac output, stroke volume, heart rate, mean arterial pressure, and +/-dP/dt were measured. Cardiomyocyte PI3K, p-Akt, Akt protein expressions and apoptosis were also determined. One-way ANOVA and Tukey's test were used for statistical analysis.
  
  
  RESULTS
  Cardiac output, stroke volume, and +/-dP/dt decreased significantly after trauma-hemorrhage. Administration of estradiol or estradiol-BSA significantly improved these parameters of cardiac function. Although trauma-hemorrhage decreased cardiomyocyte PI3K protein expression and Akt phosphorylation (p-Akt), estradiol or estradiol-BSA treatment following trauma-hemorrhage prevented such decreases in cardiomyocyte PI3K protein expressions and p-Akt. The increase in cardiomyocyte apoptosis was also prevented in rats receiving estradiol-BSA. Co-administration of ICI 182,780 or Wortmannin abolished beneficial effects of estradiol-BSA on cardiac functions following trauma-hemorrhage.
  
  
  CONCLUSIONS
  The PI3K/Akt pathway plays a critical role in mediating the nongenomic salutary effects of estradiol on cardiac function following trauma-hemorrhage.
authors.affiliation: Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294, USA.
authors.forename: Huang-Ping
authors.initials: HP
authors.lastname: Yu
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Mashkoor A
authors.initials: MA
authors.lastname: Choudhry
authors.forename: Martin G
authors.initials: MG
authors.lastname: Schwacha
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
mesh_terms: D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002302:Cardiac Output; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D000077267:Fulvestrant; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000378:metabolism*; D000077191:Wortmannin; D014947:Wounds and Injuries / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000730:Androstadienes; D004967:Estrogens; D020011:Protective Agents; D000077267:Fulvestrant; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin