Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Zhaokang Cheng; Laura A DiMichele; Mauricio Rojas; Cyrus Vaziri; Christopher P Mack; Joan M Taylor

doi:10.1016/j.yjmcc.2013.12.002

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Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Journal article

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Peer reviewed

Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Zhaokang Cheng, Laura A DiMichele, Mauricio Rojas, Cyrus Vaziri, Christopher P Mack and Joan M Taylor

Journal of molecular and cellular cardiology, Vol.67, pp.1-11

02/2014

DOI: https://doi.org/10.1016/j.yjmcc.2013.12.002

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https://hdl.handle.net/2376/109774

PMCID: PMC4237309

PMID: 24342076

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Abstract

Mitochondria

Anthracycline cardiomyopathy

Cardiomyocyte

Cell cycle

Apoptosis

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 mec6hanistic 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. [Display omitted] •Cardiac FAK depletion exacerbated DOX-induced dysfunction and myocyte apoptosis.•Activation of cardiac FAK provided protection from DOX-induced toxicity.•FAK activation preserves mitochondrial integrity by inducing p21 and Bim.

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Title: Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1
Creators: Zhaokang Cheng - Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Laura A DiMichele - Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Mauricio Rojas - McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
Cyrus Vaziri - Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Christopher P Mack - Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Joan M Taylor - Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
Publication Details: Journal of molecular and cellular cardiology, Vol.67, pp.1-11
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: Elsevier Ltd
Identifiers: 99900547268401842
Language: English
Resource Type: Journal article