Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-γ, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury
- Nassirah Khandoudi1,
- Philippe Delerive2,
- Isabelle Berrebi-Bertrand1,
- Robin E. Buckingham1,
- Bart Staels2 and
- Antoine Bril1
- 1Cardiovascular and Urogenital Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania
- 2Unit 545 Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’Athéroslérose, Institut Pasteur de Lille, and Faculté de Pharmacie, Université de Lille II, Lille, France
Abstract
This study was conducted to evaluate whether treatment of normal and diabetic rat hearts with rosiglitazone, a high-affinity ligand of the peroxisome proliferator-activated receptor-γ (PPAR-γ) used for the treatment of type 2 diabetes, improves postischemic functional recovery. The effects of acute rosiglitazone administration were investigated using working hearts isolated from normal rat or rats diabetic for 4 weeks after streptozotocin (STZ) injection. Hearts were subjected to 30 min of normothermic, zero-flow ischemia followed by 30-min reperfusion. Rosiglitazone (1 μmol/l) administered before ischemia had no effect on cardiac function during baseline perfusion, but it significantly improved aortic flow during reperfusion in both normal and diabetic hearts. In a chronic protocol in which rosiglitazone was given by daily gavage (10 μmol/kg body wt) immediately after STZ injection, rosiglitazone also prevented postischemic injury and significantly improved functional recovery. Using Western immunoblotting, it was demonstrated that the acute cardioprotective effect of rosiglitazone is associated with an inhibition of Jun NH2-terminal kinase phosphorylation in both normal and diabetic rat hearts. Furthermore, rosiglitazone also inhibited activating protein-1 DNA-binding activity. These data, demonstrating that rosiglitazone limits postischemic injury in isolated hearts, suggest an important function for PPAR-γ in the heart.
Footnotes
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Address correspondence and reprint requests to Antoine Bril, PhD, Cardiovascular and Urogenital Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Rd., P.O. Box 1539, UW2511, King of Prussia, PA 19406. E-mail: antoine_bril{at}gsk.com.
Received for publication 17 January 2001 and accepted in revised form 15 February 2002.
N.K. and P.D. contributed equally to this work.
AP-1, activating protein-1; JNK, Jun NH2-terminal kinase; LDH, lactate dehydrogenase; MAP, mitogen-activated protein; P-JNK, phosphorylated form of JNK; PPAR-γ, peroxisome proliferator-activated receptor-γ; STZ, streptozotocin; TBST, Tris-buffered saline with Tween.
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