PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation.
Cardiovascular disease (CVD) is a leading cause of death and disabilities worldwide. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists possess potent anti-inflammatory actions and have recently emerged as potential therapeutic agents for CVD. Here we show that H2O2 induced apoptosis in cardiomyocytes with a marked down-regulation of Bcl-2 protein. The PPARgamma agonist rosiglitazone protected cardiomyocytes from oxidative stress and apoptosis. Cardiomyocytes constitutively overexpressing PPARgamma were resistant to oxidative stress-induced apoptosis and protected against impairment of mitochondrial function. On the contrary, cells expressing a dominant negative mutant of PPARgamma were highly sensitive to oxidative stress. Cells overexpressing PPARgamma exhibited an almost 3 fold increase in Bcl-2 protein content; whereas, in PPARgamma dominant negative expressing cells, Bcl-2 was barely detected. Bcl-2 knockdown by siRNA in cells overexpressing PPARgamma results in increased sensitivity to oxidative stress, suggesting that Bcl-2 up-regulation mediated the protective effects of PPARgamma. These data suggest that, in oxidative stress-induced cardiomyocyte apoptosis, PPARgamma protects cells from oxidative stress through upregulating Bcl-2 expression. These findings provide further support for the use of PPARgamma agonists in ischemic cardiac disease.
Ren
Yusheng
Y
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China. renyusheng@gmail.com
Sun
Chengbo
C
Sun
Yan
Y
Tan
Hongbing
H
Wu
Yuechun
Y
Cui
Bo
B
Wu
Zonggui
Z
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002316:Cardiotonic Agents / Q000819:agonists / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000188:drug therapy; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000633:toxicity; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D002316:Cardiotonic Agents; D061945:Caspase Inhibitors; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D053148:Caspase 3