Estrogen suppresses cardiac IL-6 after trauma-hemorrhage via a hypoxia-inducible factor 1 alpha-mediated pathway.

Abstract

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 17beta-estradiol (estrogen) after trauma-hemorrhage normalized cardiac IL-6 levels and restored cardiac functions under those conditions. Because hypoxia-inducible factor (HIF) 1 alpha is expressed during hypoxia and cellular stress and up-regulates the expression of IL-6, we hypothesized that HIF-1 alpha 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-alpha 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-1 alpha, and nuclear factor (NF) kappaB activities were measured. IL-6, NF-kappaB, and HIF-1 alpha levels were markedly elevated after trauma-hemorrhage; all of these parameters were normalized by estrogen as well as YC-1 administration after trauma-hemorrhage. 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-1 alpha. In addition, estrogen decreased the elevated HIF-1 alpha, NF-kappaB, 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-1 alpha expression and activity.

• Authors: Eike A Nickel, Chi-Hsun Hsieh, Jianguo G Chen, Martin G Schwacha, Irshad H Chaudry
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 31 Issue 4 Pg. 354-8 (Apr 2009) ISSN: 1540-0514 [Electronic] United States
• PMID: 18791496 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Estrogens
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-6
• RNA, Messenger

Topics

• Animals
• Disease Models, Animal
• Estrogens (pharmacology)
• Heart (drug effects, physiopathology)
• Hemorrhage (blood, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Interleukin-6 (blood, genetics)
• Mice
• Mice, Inbred C3H
• RNA, Messenger (genetics)
• Resuscitation
• Reverse Transcriptase Polymerase Chain Reaction
• Wounds and Injuries (blood, physiopathology)