AKAP-Lbc mediates protection against doxorubicin-induced cardiomyocyte toxicity.

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State: Public
Version: Author's accepted manuscript
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Serval ID
serval:BIB_905B4AA97660
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
AKAP-Lbc mediates protection against doxorubicin-induced cardiomyocyte toxicity.
Journal
Biochimica et Biophysica Acta. Molecular Cell Research
Author(s)
Caso S., Maric D., Arambasic M., Cotecchia S., Diviani D.
ISSN
0006-3002 (Print)
ISSN-L
0167-4889
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
1864
Number
12
Pages
2336-2346
Language
english
Abstract
Doxorubicin (DOX) is a chemotherapic agent that is widely used to treat hematological and solid tumors. Despite its efficacy, DOX displays significant cardiac toxicity associated with cardiomyocytes death and heart failure. Cardiac toxicity is mainly associated with the ability of DOX to alter mitochondrial function. The current lack of treatments to efficiently prevent DOX cardiotoxicity underscores the need of new therapeutic approaches. Our current findings show that stimulation of cardiomyocytes with the α1-adrenergic receptor (AR) agonist phenylephrine (PE) significantly inhibits the apoptotic effect of DOX. Importantly, our results indicate that AKAP-Lbc is critical for transducing protective signals downstream of α1-ARs. In particular, we could show that suppression of AKAP-Lbc expression by infecting primary cultures of ventricular myocytes with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly impairs the ability of PE to reduce DOX-induced apoptosis. AKAP-Lbc-mediated cardiomyocyte protection requires the activation of anchored protein kinase D1 (PKD1)-dependent prosurvival pathways that promote the expression of the anti-apoptotic protein Bcl2 and inhibit the translocation of the pro-apoptotic protein Bax to mitochondria. In conclusion, AKAP-Lbc emerges as a coordinator of signals that protect cardiomyocytes against the toxic effects of DOX.
Keywords
A-kinase anchoring protein (AKAP), Adrenergic receptors, Cardiomyocyte, Doxorubicin, Protein kinase a, Signal transduction
Pubmed
Web of science
Funding(s)
Swiss National Science Foundation / Projects
Create date
11/12/2017 17:21
Last modification date
17/09/2020 8:17
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