Estrogen suppresses cardiac IL-6 after trauma-hemorrhage via a hypoxia-inducible factor 1 alpha-mediated pathway.
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.
Nickel
Eike A
EA
Department of Surgery, Center for Surgical Research, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
Hsieh
Chi-Hsun
CH
Chen
Jianguo G
JG
Schwacha
Martin G
MG
Chaudry
Irshad H
IH
D000818:Animals; D004195:Disease Models, Animal; D004967:Estrogens / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006470:Hemorrhage / Q000097:blood / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000235:genetics; D012151:Resuscitation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014947:Wounds and Injuries / Q000097:blood / Q000503:physiopathology*
D004967:Estrogens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D012333:RNA, Messenger
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