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
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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.
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Studies in nondiabetic rats have shown a positive benefit of TZD treatment upon ischemia/reperfusion, although this has not been shown to be true for other models such as pigs.
“Studies in nondiabetic rats have also shown a positive benefit of TZD treatment upon ischemia/reperfusion (158, 176, 390), although this has not been shown to be true for other models such as pigs (380).”
From Cardiac remodeling in obesity (2008) · cites this paper as [176]
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References 33 · Cited by 174
- Authors
- Khandoudi, N., Delerive, P., Berrebi-Bertrand, I., Buckingham, R. E., Staels, B., & Bril, A.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Inserm (FR)
- Cardiovascular and Urogenital Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-05-01
- Volume
- 51
- Issue
- 5
- Pages
- 1507-1514
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2107326660
- Cited by
- 174
- References
- 33
- Citations by year
- 2025: 4 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 2 · 2014: 10 · 2013: 9 · 2012: 7
- FWCI
- 11.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- rosiglitazone, PPARγ, JNK phosphorylation, AP-1 DNA binding, myocardial ischemia-reperfusion injury, cardioprotection, diabetic cardiomyopathy, streptozotocin-induced diabetes
- MeSH terms
- Rosiglitazone, Animals, Cardiotonic Agents, Carrier Proteins, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Glucose, Hypoglycemic Agents, Male, Monosaccharide Transport Proteins, Muscle Proteins, Myocardium, Thiazoles, Transcription Factors, Myocardial Reperfusion Injury, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Lactic Acid, Mitogen-Activated Protein Kinases, Thiazolidinediones, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Glucose Transporter Type 4, Rats, In Vitro Techniques
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