A role of PPAR-gamma in androstenediol-mediated salutary effects on cardiac function following trauma-hemorrhage.
OBJECTIVE
To examine the mechanism by which androstenediol improves cardiac function following trauma-hemorrhage (T-H).


BACKGROUND
Androstenediol administration improves cardiovascular function and attenuates proinflammatory cytokine production following T-H. Activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to be protective following ischemic conditions. We hypothesized that PPAR-gamma activation plays a role in the androstenediol-mediated salutary effects on cardiac function following T-H.


METHODS
Male rats underwent laparotomy and hemorrhagic shock (40 mm Hg for 90 minutes), followed by resuscitation with 4 times the shed blood volume in the form of Ringer's lactate. Androstenediol (1 mg/kg body weight, i.v.) was administrated at the end of resuscitation. In a separate group of animals, a PPAR-gamma antagonist (GW9662) was administered simultaneously with androstenediol and animals were killed at 5 hours thereafter.


RESULTS
A decrease in cardiac function and an increase in IL-6 and iNOS gene expression were observed following T-H. Androstenediol treatment normalized cardiac function, increased PPAR-gamma DNA binding activity, attenuated IL-6 and iNOS gene expressions, and reduced plasma IL-6. Plasma 15-deoxy-Delta12, 14-prostaglandin J2 (PGJ2, an endogenous PPAR-gamma agonist) levels were also increased in androstenediol-treated T-H rats, but these levels were lower than those observed in shams. Coadministration of PPAR-gamma antagonist along with androstenediol, however, prevented the androstenediol-mediated reduction in cardiac iNOS and IL-6 expressions and abolished the improvements in cardiac function.


CONCLUSIONS
The androstenediol-mediated salutary effects on cardiac function following T-H appear to be mediated at least in part via PPAR-gamma activation, which down-regulates IL-6 and iNOS gene expression in the heart.
Shimizu
Tomoharu
T
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Szalay
László
L
Hsieh
Ya-Ching
YC
Suzuki
Takao
T
Choudhry
Mashkoor A
MA
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D045930:Anabolic Agents / Q000494:pharmacology*; D015114:Androstenediol / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002302:Cardiac Output / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000187:drug effects*
C457499:2-chloro-5-nitrobenzanilide; D045930:Anabolic Agents; D000813:Anilides; D015850:Interleukin-6; D047495:PPAR gamma; C037112:9-deoxy-delta-9-prostaglandin D2; D015114:Androstenediol; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2