Document Detail

The PPAR-gamma agonist rosiglitazone facilitates Akt rephosphorylation and inhibits apoptosis in cardiomyocytes during hypoxia/reoxygenation.
MedLine Citation:
PMID:  19732122     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND AIM: Results on the cardiovascular effects of PPAR-gamma agonists are conflicting. On one hand, it was suggested that the PPAR-gamma agonist rosiglitazone may increase the risk of cardiovascular events. On the other hand, PPAR-gamma agonists reduce myocardial infarct size and improve myocardial function during ischemia/reperfusion in animal studies in vivo. However, the mechanism of this effect is unclear, and it is open if PPAR-gamma agonists have a direct effect on cardiac myocyte survival in ischemia/reperfusion. The aim of this study was to determine the effect of the PPAR-gamma agonist rosiglitazone on hypoxia/reoxygenation-induced apoptosis of isolated cardiomyocytes.
METHODS: Isolated rat cardiac myocytes were pretreated with rosiglitazone or vehicle for 30 min before they were subjected to hypoxia for 4 h followed by different times of reoxygenation (5 min to 12 h). Apoptosis was determined by in situ hybridization for DNA fragmentation (TUNEL) as well as detection of cytoplasmic accumulation of histone-associated DNA fragments by enzyme-linked immunosorbent assay (ELISA). Activation of apoptosis regulating intracellular signalling pathways was studied by immunoblotting using phosphospecific antibodies.
RESULTS: Rosiglitazone significantly reduced apoptosis of isolated cardiomyocytes subjected to hypoxia/reoxygenation, independently determined with two methods. After 4 h of hypoxia and 12 h of reoxygenation, 34 +/- 3.6% of the vehicle treated cardiac myocytes stained positive for DNA fragmentation in the TUNEL staining. Rosiglitazone treatment reduced this effect by 23% (p < 0.01). Even more pronounced, cytoplasmic accumulation of histone-associated DNA fragments detected by ELISA was reduced by 35% (p < 0.05) in the presence of rosiglitazone. This inhibition of hypoxia/reoxygenation-induced apoptosis was associated with an increased reoxygenation-induced rephosphorylation of the protein kinase Akt, a crucial mediator of cardiomyocyte survival in ischemia/reperfusion of the heart. This effect was reversed by GW-9662, an irreversible PPAR-gamma antagonist. However, rosiglitazone did not alter phosphorylation of the MAP kinases ERK1/2 and c-Jun N-terminal kinase (JNK).
CONCLUSION: It can be concluded that cardiac myocytes are direct targets of PPAR-gamma agonists promoting its survival in ischemia/reperfusion, at least in part by facilitating Akt rephosphorylation. This effect may be of clinical relevance inhibiting the reperfusion-induced injury in patients suffering from myocardial infarction or undergoing cardiac surgery.
H Kilter; M Werner; C Roggia; J-C Reil; H-J Schäfers; U Kintscher; M Böhm
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-03
Journal Detail:
Title:  Diabetes, obesity & metabolism     Volume:  11     ISSN:  1463-1326     ISO Abbreviation:  Diabetes Obes Metab     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-09-30     Completed Date:  2011-01-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100883645     Medline TA:  Diabetes Obes Metab     Country:  England    
Other Details:
Languages:  eng     Pagination:  1060-7     Citation Subset:  IM    
Klinik für Innere Medizin III, Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
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MeSH Terms
Analysis of Variance
Apoptosis / drug effects*
Cell Hypoxia / drug effects*
Hypoglycemic Agents / pharmacology*
Myocytes, Cardiac / drug effects*,  physiology
Proto-Oncogene Proteins c-akt / drug effects*,  metabolism
Rats, Sprague-Dawley
Thiazolidinediones / pharmacology*
Reg. No./Substance:
0/Hypoglycemic Agents; 0/Thiazolidinediones; 122320-73-4/rosiglitazone; EC Proteins c-akt

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