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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Neonatal rat ventricular myocytes (NRVMs) were treated with clinical doses (low: 2 \u03bcM; high: 5 \u03bcM) of imatinib and assessed for molecular changes. Imatinib increased peak systolic Ca<jats:sup>2+<\/jats:sup> and Ca<jats:sup>2+<\/jats:sup> transient decay rates and Western analysis revealed significant increases in phosphorylation of phospholamban (Thr\u201017) and the ryanodine receptor (Ser\u20102814), signifying activation of calcium\/calmodulin\u2010dependent 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\u20103 cleavage, indicating a necrotic mechanism of death in myocytes. We expressed AdNFATc3\u2010green 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data show that imatinib can activate pathological hypertrophic signaling pathways by altering intracellular Ca<jats:sup>2+<\/jats:sup> dynamics. This is likely a contributing mechanism for the adverse cardiac effects of imatinib.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cts.12173","type":"journal-article","created":{"date-parts":[[2014,6,17]],"date-time":"2014-06-17T00:10:43Z","timestamp":1402963843000},"page":"360-367","source":"Crossref","is-referenced-by-count":16,"title":["Imatinib Activates Pathological Hypertrophy by Altering Myocyte Calcium Regulation"],"prefix":"10.1111","volume":"7","author":[{"given":"Larry A.","family":"Barr","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center Temple University School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Makarewich","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center Temple University School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remus 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