Imatinib activates pathological hypertrophy by altering myocyte calcium regulation

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Larry A Barr1, Catherine A Makarewich, Remus M Berretta

  • 1Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.

Clinical and Translational Science
|June 17, 2014
PubMed
Abstract

Insights

Imatinib treatment alters calcium handling in heart cells, leading to pathological cardiac hypertrophy. This study reveals imatinib

Area of Science:

  • Cardiology
  • Oncology
  • Molecular Biology

Background:

  • Imatinib mesylate is a tyrosine-kinase inhibitor used for cancers like chronic myelogenous leukemia.
  • Evidence suggests imatinib can cause cardiotoxicity in cancer patients.
  • This study investigates imatinib's potential to alter calcium regulation and promote cardiac hypertrophy.

Purpose of the Study:

  • To investigate the effects of imatinib on intracellular calcium handling in neonatal rat ventricular myocytes (NRVMs).
  • To determine if imatinib induces pathological cardiac hypertrophy through altered calcium regulatory mechanisms.

Main Methods:

  • NRVMs were treated with clinical doses of imatinib (2 μM and 5 μM).
  • Assessed molecular changes including calcium transients, protein phosphorylation (phospholamban, ryanodine receptor), and atrial natriuretic peptide abundance.
  • Evaluated NRVM volume, myocyte surface area, and cell death mechanisms (apoptosis vs. necrosis).
  • Measured nuclear factor of activated T cells (NFATc3) translocation.

Main Results:

  • Imatinib increased peak systolic Ca(2+) and Ca(2+) transient decay rates.
  • Significant increases in phospholamban and ryanodine receptor phosphorylation indicated calcium/calmodulin-dependent kinase II (CaMKII) activation.
  • Imatinib increased NRVM volume, myocyte surface area, and atrial natriuretic peptide levels.
  • Cell death occurred via necrosis, not apoptosis.
  • Imatinib promoted NFATc3 translocation, which was inhibited by FK506 or CaMKII inhibitors.

Conclusions:

  • Imatinib activates pathological hypertrophic signaling pathways by disrupting intracellular Ca(2+) dynamics.
  • Altered calcium handling is a likely mechanism contributing to imatinib-induced adverse cardiac effects.
Keywords:
calciumcancer pharmacologyhypertrophymolecular biology

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