Thesis

The role of map kinase phosphatase-2 (MKP-2) in cardiac function

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Awarding institution
  • University of Strathclyde
Date of award
  • 2010
Thesis identifier
  • T12736
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Abstract
  • Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type I dual specific phosphatase that functions to regulate the activity of the ERK and JNK. The MAPKs are a large class of enzymes involved in mediating a number of physiological and pathological changes in the heart. This project utilized a novel MKP-2 knockout mouse and investigated the effects of MKP- 2 deletion on MAPK-mediated signalling and cellular proliferation and correlated these findings with effects on cardiac phenotype and function. Experiments in MEFs demonstrated that in response to serum, MKP-2 induction was dependent on prior ERK activation in wild type MEFs but not JNK or p38 MAPK. It was established that cell growth was substantially reduced in MKP-2-/- MEFs which was linked with significant increase in cell doubling time. Over-expression of Adv.MKP-2 reversed the deficit in cell growth. Analysis of the cell cycle showed that these cells were delayed in G2/M phase which was associated with enhanced accumulation of cyclin B1 and increased phosphorylation of cdc-2 kinase. MEFs derived from MKP-2-/- mice displayed increased apoptosis in response to anisomycin which correlated with enhanced caspase-3 cleavage and phosphorylation of γH2AX. In addition, over-expression of Adv.MKP-2 reversed the enhanced apoptosis in MKP-2-/- MEFs which correlated with specific inhibition of JNK signalling. Similar to the findings in MEFs, CF exhibited decreased cellular proliferation. However, assessment of these mice using echocardioraphy in vivo revealed that the LVESD, LVEDD were increased in the KO mice compared with the wild type littermates. In contrast, FS was decreased in the KO compared with the wild type. Analysis of the MTAB heart homogenates demonstrated that MKP-2 expression was decreased in MTAB in comparison to sham operated animals. In contrast, ERK phosphorylation was transiently increased in MTAB compared with sham operated animals. This current study has established that MKP-2 plays an important role in cell proliferation and survival, regulating both cell cycle progression and apoptosis. It also suggests that MKP-2 can influence growth characteristics of cardiac fibroblasts and this has the potential to regulate heart size and possibly myocyte function.
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DOI
Date Created
  • 2010
Former identifier
  • 820729

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