198 Involvement of Mitogen Activated Kinase Kinase 7 in Tyrosine Kinase Inhibitor Induced Myocardial Injury. (6th June 2015) - Maddock, Helen
Abstract : Introduction: Mitogen Activated Protein (MAP) kinase signalling cascades play significant roles in the development of cardiac hypertrophy in response to external stresses. Mitogen activated kinase kinase 7 (MKK7) is a selective upstream regulator of the c-Jun N-terminal kinase (JNK) pathway. Specific over expression of MKK7 in hearts has been shown to increase the sensitivity of cardiomyocytes to external stresses. We investigated the expression and activation levels of MKK7 at mRNA and protein level; in particular, investigating the level of MKK7 phosphorylation in response to external stresses induced by the tyrosine kinase receptor inhibitor Sunitinib. Although this Sunitinib has been shown to be highly effective in the treatment of cancers such as metastatic renal-cell carcinoma and gastrointestinal stromal tumours, adverse cardiovascular events have been reported in treated patients. Methods: Langendorff perfused hearts were perfused with vehicle (normoxic control) or Sunitinib for 120 min and either stained with triphenyl-tetrazolium chloride to assess the level of infarct to risk size (n = 4) or analysed by real time PCR for the expression profile of MKK7 mRNA (n = 6) or analysed by western blot to assess the level of MKK7 activation (n = 4). Results: TTC staining revealed that Sunitinib causes a significant increase in infarct size compared to a normoxic control group (vehicle=5.4 ± 2%; Sunitinib=46 ± 4.5%, P < 0.0001). mRNA levels of MKK7 remained unchanged. However, an increase in phosphorylated MKK7 (p-MKK7) levels were detected. Conclusion: The increase in p-MKK7 expression directly correlates with Sunitinib induced cardiotoxicity, suggesting that MKK7 could be an important intracellular signalling protein involved in tyrosine kinase inhibitor induced cardiotoxicity.