P59Identification of A Kinase Interacting Protein 1 (AKIP1) as a novel cardiac hypertrophy gene

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Abstract

Purpose

Heart failure (HF) is a complex disease and is accompanied by profound changes in gene expression patterns. We recently performed a multi-model gene expression analysis and identified A Kinase Interacting Protein 1 (AKIP1) as a HF associated gene. Here we confirm the up-regulation of this gene in different HF and hypertrophy models. We also show the basic characterization of AKIP1 and its potential role in hypertrophy development.

Methods

Using Real-time PCR (RT-PCR) AKIP1 mRNA expression was analysed in a post-MI rat HF model and in hypertensive Ren-2 transgenic rats that develop HF. In addition expression was analysed in primary isolated neonatal rat cardiomyocytes stimulated with hypertrophy inducing hormones (phenylephrine (PE), isoproterenol (Iso) and endothelin-1 (ET-1)). To investigate the function of AKIP1 overexpression and Silencing studies were performed in isolated cardiomyocytes and protein synthesis, cell growth (cell surface area) and RNA expression profiles were analysed. Western blot analysis was performed to investigate potential AKIP1 related signaling pathways.

Results

RT-PCR analyses showed that AKIP1 was significantly up-regulated in all hypertrophy and HF models. This confirms previous microarray data and shows that AKIP1 is a HF associated gene. AKIP1 overexpression in cardiomyocytes revealed more contracting cells and immunofluorescence microscopy showed that these cells have a more organized actin/sarcomere structure. Overexpressing cells also showed an increased cells size and protein synthesis analysis confirmed the AKIP1 hypertrophy inducing effect. Silencing of AKIP1 could, however, not prevent PE induced hypertrophy, suggesting that AKIP1 functions in a different pathway. Initial cell signaling pathway analysis has been performed suggesting a link between AKIP1 and the NFAT phosphorylation state.

Conclusion

AKIP1 is a novel HF associated gene and overexpression of AKIP1 in cardiomyocytes can induce hypertrophy, at least in vitro. Initial pathway analysis indicates that AKIP1 may operate via established hypertrophy inducing pathways.

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