Adjudication committee
- First opponent: Reader James Whiteford, Queen Mary University of London, UK
- Second opponent: Professor Elisabeth Ehler, King’s College London, UK
- Third member and chair of the evaluation committee: Associate Professor Kjetil Wessel Andressen, University of Oslo
Chair of the Defence
Professor Håvard Attramdal, University of Oslo
Principal Supervisor
Researcher Cathrine Rein Carlson, University of Oslo
Summary
The heart’s function is to pump to facilitate the transportation of blood filled with oxygen and nutrients to our vital organs. For the heart to perform its function, cardiomyocytes need to respond to various stimuli. One way cardiomyocytes do so is through transmembrane-bound proteins which facilitate intracellular signaling in response to the mechanical and biochemical stimuli they receive. One such transmembrane protein is syndecan-4.
This thesis has investigated the molecular network downstream of syndecan-4 to better understand its function in the heart. The presented thesis investigated several syndecan-4 binding partners and their associated signaling networks, namely Akt, β-parvin, and Muscle LIM Protein (MLP). In the heart, Akt signaling is known to be involved in the control of cell growth and metabolism, β-parvin signaling is known for its role in cardiomyocyte geometry regulation, and mutations in MLP are known to cause hypertrophic and dilated cardiomyopathy in humans.
The thesis used various molecular biology methods such as binding assays, protein level analysis, microscopy, and subcellular localization studies in left-ventricular tissue and isolated cardiomyocytes from rats and syndecan-4 knockout (KO) and wild-type mice, and cell lines. Through these methods, we identified a role for syndecan-4 in Akt, β-parvin, and MLP signaling in the heart.
The loss of syndecan-4 caused alterations in the downstream Akt and β-parvin signaling networks, and cardiomyocytes exhibited a reduction in cardiomyocyte area and length. However, certain molecular changes and cardiomyocyte size and length reductions were only present in female syndecan-4 KO mice, while males remained unaffected. We also found that syndecan-4 binds to MLP in the nucleus of rat cardiomyocytes, and this binding was reduced with certain MLP mutations known to cause hypertrophic cardiomyopathy in humans.
Overall, this suggests that syndecan-4 plays an important signaling role in the heart and that its role is sex-dependent.
