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Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage: Akt-dependent HO-1 up-regulation*

Hsu, Jun-Te MD; Kan, Wen-Hong MD, PhD; Hsieh, Chi-Hsun MD; Choudhry, Mashkoor A. PhD; Bland, Kirby I. MD; Chaudry, Irshad H. PhD

doi: 10.1097/CCM.0b013e3181a030ce
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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.

From the Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham.

Permanent address for Jun-Te Hsu: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Supported, in part, by the National Institutes of Health (Bethesda, MD) grant R37 GM39519.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: Irshad.Chaudry@ccc.uab.edu

© 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins