Rosiglitazone-induced myocardial protection against ischaemia-reperfusion injury is mediated via a phosphatidylinositol 3-kinase/Akt-dependent pathway.
1. Rosiglitazone is widely used in the treatment of Type 2 diabetes. However, in recent years it has become evident that the therapeutic effects of peroxisome proliferator-activated receptor gamma ligands reach far beyond their use as insulin sensitizers. Recently, the ability of rosiglitazone pretreatment to induce cardioprotection following ischaemia-reperfusion (I/R) has been well documented; however, the protective mechanisms have not been elucidated. In the present study, examined the role of the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway in rosiglitazone cardioprotection following I/R injury. 2. Mice were pretreated with 3 mg/kg per day rosiglitazone for 14 days before hearts were subjected to ischaemia (30 min) and reperfusion (2 h). Wortmannin (1.4 mg/kg, i.p.), an inhibitor of PI3-K, was administered 10 min prior to myocardial I/R. Then, activation of the PI3-K/Akt/glycogen synthase kinase (GSK)-3alpha signalling pathway was examined. The effects of PI3-K inhibition on rosiglitazone-induced cardioprotection were also evaluated. 3. Compared with control rats, the ratio of infarct size to ischaemic area (area at risk) and the occurrence of sustained ventricular fibrillation in rosiglitazone-pretreated rats was significantly reduced (P < 0.05). Rosiglitazone pretreatment attenuated cardiac apoptosis, as assessed by ELISA to determine cardiomyocyte DNA fragmentation. Rosiglitazone pretreatment significantly increased levels of phosphorylated (p-) Akt and p-GSK-3alpha in the rat myocardium. Pharmacological inhibition of PI3-K by wortmannin markedly abolished the cardioprotection induced by rosiglitazone. 4. These results indicate that rosiglitazone-induced cardioprotection in I/R injury is mediated via a PI3-K/Akt/GSK-3alpha-dependent pathway. The data also suggest that modulation of PI3-K/Akt/GSK-3alpha-dependent signalling pathways may be a viable strategy to reduce myocardial I/R injury.
Zhang
Xue-Jiao
XJ
Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Xiong
Zi-Bo
ZB
Tang
An-Li
AL
Ma
Hong
H
Ma
Yue-Dong
YD
Wu
Jing-Guo
JG
Dong
Yu-Gang
YG
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000201:enzymology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D047495:PPAR gamma / Q000819:agonists; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000201:enzymology / Q000517:prevention & control; D000077191:Wortmannin
D000730:Androstadienes; D001786:Blood Glucose; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000077191:Wortmannin