AbstractHeart failure is the most frequent cause of mortality and morbidity in industrialized nations. Prolonged pressure overload due to hypertension as well as valvular and ischemic heart diseases leads to compensatory hypertrophy and heart failure. The objective of this literature thesis is to provide detailed insight into a particular molecular mechanism important for development of hypertrophy and subsequent heart failure, which is an incompletely understood process. A hypothesis for development of hypertrophy and progression to failure is that the sarcomeric Z-disc proteins, among them the transmembrane proteoglycan syndecan-4, are essential molecular players. This hypothesis has been tested over the last ten years at the Institute for Experimental Medical Research (IEMR) at Oslo University Hospital Ullevål, and by a few other groups. Thus, syndecan-4 has been the focus of this thesis. By using genetically modified mice, a research group at the IEMR showed that mice lacking syndecan-4 did not develop concentric myocardial hypertrophy after being exposed to pressure overload, whereas in wild-type mice substantial hypertrophy was found, as expected. Moreover, following pressure overload, syndecan-4−∕− mice showed a decreased activation of the pro-hypertrophic signaling molecule, nuclear factor of activated T-cells (NFAT) compared to wild-type mice. NFAT is a central intracellular signaling molecule involved in development of hypertrophy. In cell culture experiments, cardiomyocytes lacking syndecan-4 displayed diminutive activation of NFAT in comparison to control cells, following 24 hours of mechanical stress. The results suggest that syndecan-4 acts as a mechanotransducer in the process of hypertrophy, activating pro-hypertrophic NFAT transcription factors in individual cardiomyocytes. Thus, syndecan-4 is thought to play an important role during development of heart failure in response to increased mechanical stress in the myocardium.