Alex Thesis

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Finsen AV.

MOLECULAR MECHANISMS IN HEART FAILURE. THE ROLE OF SYNDECAN-4 IN DEVELOPMENT OF MYOCARDIAL HYPERTROPHY AND HEART FAILURE

Thesis 2008, Faculty of Medicine, Oslo University

DOKTORAND: Cand. med. Alexandra Vanessa Finsen

GRAD: Dr. med
FAKULTET: Det medisinske fakultet, Universitetet i Oslo

INSTITUTT: Institutt for eksperimentell medisinsk forskning, Ullevål universitetssykehus

VEILEDER/E:       Professor Geir Christensen
DISPUTAS:            06.06.2008

English summary:

The prevalence of congestive heart failure (CHF) is increasing dramatically world-wide, and its management has vast socioeconomic implications. Sustained myocardial hypertrophy is an important risk factor for developing CHF, but the underlying mechanisms initiating and maintaining hypertrophy are still poorly understood. The aim of this thesis was to identify such underlying molecular mechanisms contributing to pathological hypertrophy and heart failure.

We demonstrate a crucial role for the membrane protein syndecan-4 in development of concentric hypertrophy in response to pressure overload, probably due to its activation of the important pro-hypertrophic calcineurin-nuclear factor of activated T cell (NFAT) pathway. In contrast to wild type mice (WT), syndecan-4^-/- mice (Syn-4^-/-) showed no development of concentric hypertrophy following aortic-banding. The calcineurin-NFAT pathway was specifically inhibited in Syn-4^-/- during pressure overload. We were able to demonstrate that syndecan-4 binds calcineurin, and the respective binding domains were identified. Moreover, a short cell-permeable blocking-peptide, specific for the syndecan-4-calcineurin interaction, was generated and significantly inhibited calcineurin-NFAT signaling. We therefore believe that syndecan-4 may represent a novel target for treatment of myocardial hypertrophy and heart failure.