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). SUMMARY BACKGROUND DATA: 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. CONCLUSION: 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.[1]References
- A role of PPAR-gamma in androstenediol-mediated salutary effects on cardiac function following trauma-hemorrhage. Shimizu, T., Szalay, L., Hsieh, Y.C., Suzuki, T., Choudhry, M.A., Bland, K.I., Chaudry, I.H. Ann. Surg. (2006) [Pubmed]
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