AKAP-Lbc mediates protection against doxorubicin-induced cardiomyocyte toxicity

Biochim Biophys Acta Mol Cell Res. 2017 Dec;1864(12):2336-2346. doi: 10.1016/j.bbamcr.2017.09.007. Epub 2017 Sep 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / genetics*
  • A Kinase Anchor Proteins / metabolism
  • Adrenergic alpha-1 Receptor Agonists / administration & dosage
  • Apoptosis / drug effects*
  • Doxorubicin / adverse effects*
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Lentivirus / genetics
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / metabolism
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Neoplasms / complications
  • Neoplasms / drug therapy
  • Phenylephrine / administration & dosage
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / drug effects


  • A Kinase Anchor Proteins
  • AKAP13 protein, human
  • Adrenergic alpha-1 Receptor Agonists
  • Minor Histocompatibility Antigens
  • Proto-Oncogene Proteins
  • Phenylephrine
  • Doxorubicin