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Imatinib activates pathological hypertrophy by altering myocyte calcium regulation. | LitMetric

AI Article Synopsis

  • Imatinib mesylate, a drug used primarily for treating chronic myelogenous leukemia, may cause heart damage by affecting calcium regulation in heart cells.
  • In experiments with neonatal rat heart cells, imatinib was found to increase calcium levels and activate related proteins, leading to cell growth and signs of cardiac hypertrophy (enlargement of heart muscle).
  • The study suggests that imatinib causes cell death through a non-apoptotic (necrotic) process and highlights that this calcium disruption could be a key reason for its harmful effects on the heart.

Article Abstract

Background: Imatinib mesylate is a selective tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably chronic myelogenous leukemia. There is evidence that imatinib can induce cardiotoxicity in cancer patients. Our hypothesis is that imatinib alters calcium regulatory mechanisms and can contribute to development of pathological cardiac hypertrophy.

Methods And Results: Neonatal rat ventricular myocytes (NRVMs) were treated with clinical doses (low: 2 μM; high: 5 μM) of imatinib and assessed for molecular changes. Imatinib increased peak systolic Ca(2+) and Ca(2+) transient decay rates and Western analysis revealed significant increases in phosphorylation of phospholamban (Thr-17) and the ryanodine receptor (Ser-2814), signifying activation of calcium/calmodulin-dependent kinase II (CaMKII). Imatinib significantly increased NRVM volume as assessed by Coulter counter, myocyte surface area, and atrial natriuretic peptide abundance seen by Western. Imatinib induced cell death, but did not activate the classical apoptotic program as assessed by caspase-3 cleavage, indicating a necrotic mechanism of death in myocytes. We expressed AdNFATc3-green fluorescent protein in NRVMs and showed imatinib treatment significantly increased nuclear factor of activated T cells translocation that was inhibited by the calcineurin inhibitor FK506 or CaMKII inhibitors.

Conclusion: These data show that imatinib can activate pathological hypertrophic signaling pathways by altering intracellular Ca(2+) dynamics. This is likely a contributing mechanism for the adverse cardiac effects of imatinib.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213285PMC
http://dx.doi.org/10.1111/cts.12173DOI Listing

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