Prevention of hypovolemic circulatory collapse by IL-6 activated Stat3.
Half of trauma deaths are attributable to hypovolemic circulatory collapse (HCC). We established a model of HCC in rats involving minor trauma plus severe hemorrhagic shock (HS). HCC in this model was accompanied by a 50% reduction in peak acceleration of aortic blood flow and cardiomyocyte apoptosis. HCC and apoptosis increased with increasing duration of hypotension. Apoptosis required resuscitation, which provided an opportunity to intervene therapeutically. Administration of IL-6 completely reversed HCC, prevented cardiac dysfunction and cardiomyocyte apoptosis, reduced mortality 5-fold and activated intracardiac signal transducer and activator of transcription (STAT) 3. Pre-treatment of rats with a selective inhibitor of Stat3, T40214, reduced the IL-6-mediated increase in cardiac Stat3 activity, blocked successful resuscitation by IL-6 and reversed IL-6-mediated protection from cardiac apoptosis. The hearts of mice deficient in the naturally occurring dominant negative isoform of Stat3, Stat3beta, were completely resistant to HS-induced apoptosis. Microarray analysis of hearts focusing on apoptosis related genes revealed that expression of 29% of apoptosis related genes was altered in HS vs. sham rats. IL-6 treatment normalized the expression of these genes, while T40214 pretreatment prevented IL-6-mediated normalization. Thus, cardiac dysfunction, cardiomyocyte apoptosis and induction of apoptosis pathway genes are important components of HCC; IL-6 administration prevented HCC by blocking cardiomyocyte apoptosis and induction of apoptosis pathway genes via Stat3 and warrants further study as a resuscitation adjuvant for prevention of HCC and death in trauma patients.
Alten
Jeffrey A
JA
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Moran
Ana
A
Tsimelzon
Anna I
AI
Mastrangelo
Mary-Ann A
MA
Hilsenbeck
Susan G
SG
Poli
Valeria
V
Tweardy
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D020896:Hypovolemia; D015850:Interleukin-6 / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000473:pathology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism*; D012769:Shock / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
D015850:Interleukin-6; D050796:STAT3 Transcription Factor