The role of ms1 in cardiac physiology and disease

Previous work in the group identified a novel gene, designated myocyte stress 1 (ms1), which is up-regulated within 1 hour in the left ventricular following aortic banding in the rat, suggesting a possible role for ms1 in the initial signalling of the hypertrophic response. ms1 is also expressed during cardiac development and is transiently up-regulated during ischaemia-reperfusion in vitro. This suggests that ms1 may play a more widespread role in cardiac physiology.;The aim of the work in this thesis was to better understand the role of ms1 in cardiac physiology and disease through a combination of in vitro and in vivo approaches. It was demonstrated that transient over-expression of a c-Myc-ms1 fusion protein into a heart-derived rat cell line, H9c2, colocalised with actin and altered gene expression of known hypertrophic and cardioprotective markers that are target genes of the myocardin-related transcription factor (MRTF)/serum response factor (SRF) transcriptional pathway. The size of cells over-expressing ms1 significantly increased by 47% when compared to untransfected cells and over-expression of ms1 markedly inhibited staurosporine-induced apoptosis by 88%. A Cre/loxP system based construct was developed to assess the in vivo of increased ms1 expression and was confirmed to work in a cell-based system. However, two independent attempts to make a transgenic mouse over-expressing ms1 were unsuccessful despite successful integration of the transgene.;Overall the findings suggest that ms1 induces a hypertrophic response and provides cardioprotection via a MRTF-SRF signalling mechanism. The findings provide for the first time direct evidence of the involvement of ms1 in hypertrophy and cardioprotection.