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.

SUMMARY BACKGROUND DATA:

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.

CONCLUSION:

The PI3K/Akt pathway plays a critical role in mediating the nongenomic salutary effects of estradiol on cardiac function following trauma-hemorrhage.

• Authors: Huang-Ping Yu, Ya-Ching Hsieh, Takao Suzuki, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H Chaudry
• Journal: Annals of surgery (Ann Surg) Vol. 245 Issue 6 Pg. 971-7 (Jun 2007) ISSN: 0003-4932 [Print] United States
• PMID: 17522524 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Androstadienes
• Estrogens
• Protective Agents
• Fulvestrant
• Estradiol
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Wortmannin

Topics

• Analysis of Variance
• Androstadienes (pharmacology)
• Animals
• Cardiac Output
• Estradiol (analogs & derivatives, pharmacology)
• Estrogens (pharmacology)
• Fulvestrant
• Male
• Myocardium (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protective Agents (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Shock, Hemorrhagic (drug therapy, metabolism)
• Wortmannin
• Wounds and Injuries (drug therapy, metabolism)