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The Role of CaMKIIδ in Modulation of NF-κB Signalling in Normal and Hypertrophied Mouse Hearts
Ort / Verlag
ProQuest Dissertations & Theses
Erscheinungsjahr
2012
Link zum Volltext
Quelle
ProQuest Dissertations & Theses A&I
Beschreibungen/Notizen
This study has focused on (i) identifying a link between CaMKII and Nuclear Factor kappa B (NF-κB) pro-inflammatory signalling in the heart, (ii) development and characterisation of a novel minimally invasive (MTAB) model of cardiac hypertrophy in mice, and (iii) assessing alterations in both CaMKII and NF-κB signalling following hypertrophy. Importantly there has been a focus on cardiac fibroblasts (CFs) in this work. A direct interaction between CaMKIIδ and NF-κB signalling has been demonstrated at the level of inhibitory- κB kinase β (IKKβ) using Surface Plasmon Resonance (SPR). Successful development of the MTAB model has allowed assessment of hypertrophic development and progression. One week following surgery, there is evidence for both systolic and diastolic dysfunction. Characteristic features of significant cardiac hypertrophy are evident four weeks following surgery. These include an increase in heart size, cardiac contractile dysfunction and increased cardiac fibrosis. Elevated CaMKIIδ and NF-κB expression and activity correlate with impaired cardiac contractile function following hypertrophy. In parallel with increased fibrosis, evidence has been provided for increased proliferation of CFs isolated from MTAB hearts in response to agonist stimulation. Using selective inhibition of CaMKII, proliferation is reduced in CFs isolated from both sham and MTAB hearts. For the first time, this has highlighted an important role for CaMKII at the level of the CF. Findings from this study provide evidence for two novel modes of action of CaMKII in the adult heart, one at the level of pro-inflammatory signalling and the other at the level of cardiac fibrosis. Both actions highlight additional mechanisms by which increased levels of CaMKII may exert deleterious effects on cardiac function during hypertrophic adaptation and cardiac remodelling.