Cardiac dysfunction is a major concern after trauma-hemorrhage, and increased IL-6 is one of the underlying causes for producing the dysfunction. Studies have shown that administration of 17β-estradiol (estrogen) after traumahemorrhage normalized cardiac IL-6 levels and restored cardiac functions under those conditions. Because hypoxia-inducible factor (HIF) 1α is expressed during hypoxia and cellular stress and up-regulates the expression of IL-6, we hypothesized that HIF-1 α induces the increased cardiac IL-6 after trauma-hemorrhage and that estrogen suppresses this induction. To examine this, C3H/HeN mice were subjected to trauma-hemorrhage or sham operation. Vehicle, the HIF-α inhibitor YC-1 [3-(5'- hydroxymethyl-2'-furyl)-1- benzylindazole, a novel activator of platelet guanylate cyclase], or estrogen was administered to trauma-hemorrhage and sham groups during resuscitation. Mice were killed at 2 h after resuscitation, and cardiac IL-6, HIF-1α, and nuclear factor (NF) κB activities were measured. IL-6, NF-κB, and HIF-1α levels were markedly elevated after trauma-hemorrhage; all of these parameters were normalized by estrogen as well as YC-1 administration after traumahemorrhage. Because elevated IL-6 levels after trauma-hemorrhage were decreased with YC-1 treatment, it indicates that IL-6 expression in cardiomyocytes is induced via HIF-1α. In addition, estrogen decreased the elevated HIF-1 α, NF-κB, and IL-6 levels after trauma-hemorrhage. These results indicate that the beneficial effects of estrogen on cardiac function after trauma-hemorrhage seem to be mediated by the inhibition of HIF-1α expression and activity. Copyright © 2009 by the Shock Society.