Molecular Mechanisms in Heart Failure : The Role of Syndecan-4 in Development of Myocardial Hypertrophy and Heart Failure
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AbstractThe prevalence of congestive heart failure (CHF) is increasing dramatically world-wide. 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 molecular mechanisms.
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-/-. 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.
List of papers The thesis is based on the following papers:
I. Alexandra Vanessa Finsen, Per Reidar Woldbæk, Jian Li, Jiaping Wu, Torstein Lyberg, Theis Tønnessen, Geir Christensen. Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling. Physiol Genomics 16: 301-308, 2004
II. Alexandra Vanessa Finsen, Geir Christensen, Ivar Sjaastad. Echocardiographic parameters discriminating myocardial infarction with pulmonary congestion from myocardial infarction without congestion in the mouse. . J Appl Physiol 98: 680 - 689, 2005
III. Alexandra Vanessa Finsen, Even K. Østli, Marianne Lyngra, Ivar Sjaastad, Hilde O. Jarstadmarken, Ståle Nygård, Sarah A. Wilcox-Adelman, Paul F. Goetinck, Torstein Lyberg, Theis Tønnessen, Srdjan Djurovic, Cathrine R. Carlson, Geir Christensen. Syndecan-4 is essential for activation of the calcineurin-NFAT pathway and development of concentric myocardial hypertrophy.
IV. Kristin B. Andersson, Jon Arne K. Birkeland, Alexandra Vanessa Finsen, William E. Louch, Ivar Sjaastad, Yibin Wang, Ju Chen, Jeffery D. Molkentin,Kenneth R. Chien, Ole M. Sejersted, Geir Christensen. Moderate heart dysfunction in mice with inducible cardiomyocyte-specific deletion of Serca2: A role for SR-independent mechanisms