OBJECTIVES: Because administration of 17β-estradiol following trauma-hemorrhage improves cardiovascular responses, we investigated whether the salutary effects of 17β-estradiol on cardiac function are mediated via Akt-dependent heme oxygenase-1 up-regulation under those conditions. DESIGN: Experimental animal study. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats underwent trauma-hemorrhage (mean blood pressure ∼40 mm Hg for 90 mins) followed by fluid resuscitation. Before resuscitation, rats received either vehicle, 17β-estradiol (1 mg/kg), or 17β-estradiol plus the phosphoinositide 3-kinase inhibitor wortmannin (1 mg/kg). At 2 hrs after trauma-hemorrhage or sham operation, the rats were killed. MEASUREMENTS AND MAIN RESULTS: Cardiac function, heart tissue myeloperoxidase activity, cardiac and circulatory cytokine levels, cardiac intercellular adhesion molecule-1, and chemokine levels were measured. Cardiac Akt and heme oxygenase-1 were also determined. We found that 17β-estradiol prevented the trauma-hemorrhage-induced impairment in cardiac function and increase in cardiac myeloperoxidase activity. Cardiac and systemic interleukin-6 and tumor necrosis factor-α levels as well as cardiac intercellular adhesion molecule-1, cytokine-induced neutrophil chemoattractant-1, and macrophage inflammatory protein-2 contents were increased following trauma-hemorrhage, which were normalized by 17β-estradiol. Administration of 17β-estradiol following trauma-hemorrhage restored cardiac Akt phosphorylation and further increased heme oxygenase-1 expression. Coadministration of wortmannin following trauma-hemorrhage abolished the previous effects by 17β-estradiol. CONCLUSIONS: These results suggest that the 17β-estradiol-meditated improvement in cardiac function following trauma-hemorrhage occurs via Akt-dependent heme oxygenase-1 up-regulation. © 2009 Lippincott Williams & Wilkins, Inc.