Inhibition of Doxorubicin-Induced Senescence by PPARδ Activation Agonists in Cardiac Muscle Cells: Cooperation between PPARδ and Bcl6

被引:28
作者
Altieri, Paola [1 ]
Spallarossa, Paolo [2 ]
Barisione, Chiara [1 ]
Garibaldi, Silvano [1 ]
Garuti, Anna [3 ]
Fabbi, Patrizia [1 ]
Ghigliotti, Giorgio [2 ]
Brunelli, Claudio [1 ,2 ]
机构
[1] Univ Genoa, Res Ctr Cardiovasc Biol, Genoa, Italy
[2] Univ Genoa, Div Cardiol, IRCCS Univ Hosp San Martino, Genoa, Italy
[3] Univ Genoa, Dept Internal Med, Lab Cellular Therapies, I-16126 Genoa, Italy
来源
PLOS ONE | 2012年 / 7卷 / 09期
关键词
PANCREATIC BETA-CELLS; THERAPEUTIC TARGETS; ISCHEMIA/REPERFUSION INJURY; CARDIOMYOCYTE APOPTOSIS; PREMATURE SENESCENCE; H9C2; CARDIOMYOBLASTS; RECEPTOR-BETA/DELTA; DOWN-REGULATION; INFLAMMATION; EXPRESSION;
D O I
10.1371/journal.pone.0046126
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Senescence and apoptosis are two distinct cellular programs that are activated in response to a variety of stresses. Low or high doses of the same stressor, i.e., the anticancer drug doxorubicin, may either induce apoptosis or senescence, respectively, in cardiac muscle cells. We have demonstrated that PPAR delta, a ligand-activated transcriptional factor that controls lipid metabolism, insulin sensitivity and inflammation, is also involved in the doxorubicin-induced senescence program. This occurs through its interference with the transcriptional repressor protein B cell lymphoma-6 (Bcl6). Low doses of doxorubicin increase the expression of PPAR delta that sequesters Bcl6, thus preventing it from exerting its anti-senescent effects. We also found that L-165041, a specific PPAR delta activator, is highly effective in protecting cardiomyocytes from doxorubicin-induced senescence through a Bcl6 related mechanism. In fact, L-165041 increases Bcl6 expression via p38, JNK and Akt activation, and at the same time it induces the release of Bcl6 from PPAR delta, thereby enabling Bcl6 to bind to its target genes. L-165041 also prevented apoptosis induced by higher doses of doxorubicin. However, while experiments performed with siRNA analysis techniques very clearly showed the weight of Bcl6 in the cellular senescence program, no role was found for Bcl6 in the anti-apoptotic effects of L-165041, thus confirming that senescence and apoptosis are two very distinct stress response cellular programs. This study increases our understanding of the molecular mechanism of anthracycline cardiotoxicity and suggests a potential role for PPAR delta agonists as cardioprotective agents.
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页数:14
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