A role of PPAR-gamma in androstenediol-mediated salutary effects on cardiac function following trauma-hemorrhage.

Abstract

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.

• Authors: Tomoharu Shimizu, László Szalay, Ya-Ching Hsieh, Takao Suzuki, Mashkoor A Choudhry, Kirby I Bland, Irshad H Chaudry
• Journal: Annals of surgery (Ann Surg) Vol. 244 Issue 1 Pg. 131-8 (Jul 2006) ISSN: 0003-4932 [Print] United States
• PMID: 16794398 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 2-chloro-5-nitrobenzanilide
• Anabolic Agents
• Anilides
• Interleukin-6
• PPAR gamma
• 9-deoxy-delta-9-prostaglandin D2
• Androstenediol
• Nitric Oxide Synthase Type II
• Prostaglandin D2

Topics

• Anabolic Agents (pharmacology)
• Androstenediol (pharmacology)
• Anilides (pharmacology)
• Animals
• Blotting, Western
• Cardiac Output (drug effects)
• Electrophoretic Mobility Shift Assay
• Gene Expression
• Interleukin-6 (blood, metabolism)
• Male
• Myocardium (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• PPAR gamma (agonists, antagonists & inhibitors, metabolism)
• Prostaglandin D2 (analogs & derivatives, blood)
• Rats
• Rats, Sprague-Dawley
• Shock, Hemorrhagic (metabolism, physiopathology)
• Ventricular Function, Left (drug effects)