Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.).
Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.).
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DOI：
10.1016/j.yjmcc.2013.12.002
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发表时间：
2014-02
影响因子：
5
通讯作者：
Taylor, Joan M.
中科院分区：
文献类型：
--
作者：
Cheng, Zhaokang;DiMichele, Laura A.;Rojas, Mauricio;Vaziri, Cyrus;Mack, Christopher P.;Taylor, Joan M.
Clinical application of potent anthracycline anticancer drugs, especially doxorubicin (DOX), is limited by a toxic cardiac side effect that is not fully understood and preventive strategies are yet to be established. Studies in genetically modified mice have demonstrated that focal adhesion kinase (FAK) plays a key role in regulating adaptive responses of the adult myocardium to pathological stimuli through activation of intracellular signaling cascades that facilitate cardiomyocyte growth and survival. The objective of this study was to determine if targeted myocardial FAK activation could protect the heart from DOX-induced de-compensation and to characterize the underlying mechanisms. To this end, mice with myocyte-restricted FAK knock-out (MFKO) or myocyte-specific expression of an active FAK variant (termed SuperFAK) were subjected to DOX treatment. FAK depletion enhanced susceptibility to DOX-induced myocyte apoptosis and cardiac dysfunction, while elevated FAK activity provided remarkable cardioprotection. Our mechanistic studies reveal a heretofore unappreciated role for the protective cyclin-dependent kinase inhibitor p21 in the repression of the pro-apoptotic BH3-only protein Bim and the maintenance of mitochondrial integrity and myocyte survival. DOX treatment induced proteasomal degradation of p21, which exacerbated mitochondrial dysfunction and cardiomyocyte apoptosis. FAK was both necessary and sufficient for maintaining p21 levels following DOX treatment and depletion of p21 compromised FAK-dependent protection from DOX. These findings identify p21 as a key determinant of DOX resistance downstream of FAK in cardiomyocytes and indicate that cardiac-restricted enhancement of the FAK/p21 signaling axis might be an effective strategy to preserve myocardial function in patients receiving anthracycline chemotherapy.
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影响因子：
6.4
作者：
Chen, Yuying;Wang, Zhanxiang;Liang, Houjie
通讯作者：
Liang, Houjie
影响因子：
20.1
作者：
Hauck, L;Hansmann, G;von Harsdorf, R
通讯作者：
von Harsdorf, R
影响因子：
11.4
作者：
Asada, M;Yamada, T;Mizutani, S
通讯作者：
Mizutani, S
影响因子：
20.1
作者：
Clemente, Carolina F. M. Z.;Tornatore, Thais F.;Franchini, Kleber G.
通讯作者：
Franchini, Kleber G.
DOI：
10.1073/pnas.1017935108
发表时间：
2011-04-12
影响因子：
11.1
作者：
Avitabile, Daniele;Bailey, Brandi;Sussman, Mark A.
通讯作者：
Sussman, Mark A.