The Cardioprotective Effects of Preconditioning with Endotoxin, but Not Ischemia, Are Abolished by a Peroxisome Proliferator-Activated Receptor-γ Antagonist

  1. Ahila Sivarajah,
  2. Michelle C. McDonald and
  3. Christoph Thiemermann
  1. Centre for Experimental Medicine, Nephrology & Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary—University of London, Charterhouse Square, London, United Kingdom
  1. Address correspondence to:
    Professor C. Thiemermann, Centre for Experimental Medicine, Nephrology and Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary—University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom. E-mail: c.thiemermann{at}qmul.ac.uk

Abstract

We investigated whether endogenous ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ) protect the heart against ischemia-reperfusion (I/R) injury. The selective PPAR-γ antagonist GW9662 (2-chloro-5-nitrobenzanilide) was used in rat models of 1) regional myocardial I/R, 2) ischemic preconditioning, and 3) delayed cardioprotection by endotoxin. We also investigated the effects of the selective cyclooxygenase-2 inhibitor, parecoxib, on ischemic preconditioning and delayed cardioprotective effects of endotoxin. Male Wistar rats were anesthetized with sodium thiopentone. Animals were subjected to either 15 or 25 min of regional myocardial I/R and pretreated with the PPAR-γ agonist ciglitazone (0.3 mg/kg), the PPAR-γ antagonist GW9662 (1 mg/kg), or GW9662 and ciglitazone. Animals were also subjected to either 1) ischemic preconditioning alone, ischemic preconditioning, and pretreated with either GW9662 or parecoxib (20 mg/kg) or 2) lipopolysaccharide (LPS) (1 mg/kg) alone, LPS, and pretreated with ciglitazone, GW9662, or parecoxib (20 mg/kg). Myocardial infarct size was determined by p-nitroblue tetrazolium staining. The PPAR-γ antagonist GW9662 (1 mg/kg) abolished the cardioprotection afforded by the potent PPAR-γ agonist ciglitazone (0.3 mg/kg). Neither GW9662 nor parecoxib affected the cardioprotective effects of ischemic preconditioning. Pretreatment with ciglitazone did not provide additional cardioprotection to LPS-treated animals. Both GW9662 and parecoxib abolished the delayed cardioprotective effects of endotoxin. Thus, we propose that 1) endogenous ligands of PPAR-γ are being generated by myocardial ischemia in sufficient amounts to attenuate myocardial I/R injury, and 2) that cyclooxygenase-2 metabolites contribute to (or even account for) the cardioprotective effects of endotoxin (second window of protection) by acting as endogenous PPAR-γ ligands.

Footnotes

  • A.S. and this work was supported by a Ph.D. Studentship from the William Harvey Research Foundation.

  • doi:10.1124/jpet.104.080598.

  • ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; TZD, thiazolidinedione; I/R, ischemia and reperfusion; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; GW9662, 2-chloro-5-nitrobenzanilide; LPS, lipopolysaccharide; MAP, mean arterial pressure; HR, heart rate; LAD, left anterior descending; AAR, area at risk; MI, myocardial infarction; DMSO, dimethyl sulfoxide; LTA, lipoteichoic acid.

    • Received November 11, 2004.
    • Accepted February 18, 2005.
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  1. Published online before print February 25, 2005, doi: 10.1124/jpet.104.080598 JPET May 2005 vol. 313 no. 2 896-901
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