Abstract 19381: Imatinib Mesylate Modifies Induced Pathological Hypertrophy by Altering Myocyte Calcium

Background —  Imatinib mesylate (IM) is a small molecule inhibitor of the fusion protein Bcr-Abl, which causes chronic myelogenous leukemia. There is some concern that IM can induce cardiac dysfunction in cancer patients. A previous study showed that chronic treatment of adult mice with IM for 3-4 weeks leads to deterioration in contractile function and LV mass decrease. We investigated the effects of IM on neonatal rat ventricular myocytes (NRVMs). The hypothesis is that calcium regulatory mechanisms are altered to induce pathological hypertrophy. Methods and Results —  NRVMs were treated with a clinical dosage (2 µM) of IM.  Western analysis showed a significant increase in phospholamban phosphorylation at T-17, signifying activation of CaMKII. The rate of decay of the systolic Ca 2+ transient was increased, consistent with an increase in rate of Ca 2+ resequestration into the SR. Coulter counter analysis was used to determine cell size and showed that average NRVM volume increased significantly (Con-102 pl; IM-133 pl. p<0.05). Myocyte surface area also increased with IM treatment (Con-6277 μm 2 ; imatinib-10259 μm 2 p<0.05). Western analysis showed significant increases in ANP abundance, a pathological hypertrophy marker, after IM administration. NRVMs were infected with AdNFATc3-GFP and NFAT nuclear translocation was analyzed as nuclear/cytoplasmic GFP. Nuclear translocation was significantly increased with IM treatment. The calcineurin inhibitor FK506 inhibited IM induced NFAT nuclear translocation (Con-0.8162 ± 0.032; imatinib-2.233 ± 0.13; imatinib+FK506-0.6277 ± 0.037. p<0.05). Conclusions —  These data show that clinical doses of IM activate pathological hypertrophy signaling pathways by enhancing SR function. This could be a mechanism for adverse cardiac effects of IM.

• Publication year

  2012

• Venue

  Circulation

• Publication date

  2012-11-20

• Fields of study

  Medicine

• Identifiers
  DOI 10.1161/circ.126.suppl_21.a19381
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• No references are available for this paper.

• No citing papers are available for this paper.