title: Imatinib activates pathological hypertrophy by altering myocyte calcium regulation.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Barr
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.forename: Remus M
authors.initials: RM
authors.lastname: Berretta
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Constantine D
authors.initials: CD
authors.lastname: Troupes
authors.forename: Felix
authors.initials: F
authors.lastname: Woitek
authors.forename: Fabio
authors.initials: F
authors.lastname: Recchia
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D000068877:Imatinib Mesylate; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D001549:Benzamides; D050778:NFATC Transcription Factors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D002118:Calcium
keywords: calcium; cancer pharmacology; hypertrophy; molecular biology