Translational cardiac research: Importance of the matrix molecules fibromodulin and lumican in left ventricular pressure overload

Heart failure is a common, deadly and highly morbid syndrome. When the heart is exposed to stimuli such as pressure overload, it remodels. The aim of this thesis was to examine the role of the extracellular matrix proteoglycans fibromodulin and lumican in cardiac remodeling in response to cardiac pressure overload. These molecules bind to fibrillar collagens in the matrix surrounding the cardiomyocytes in the heart, and are thought to be involved in wound healing and scarring. Cardiac fibrosis is a central remodeling process of the heart, impairing cardiac function. Thus, a better understanding of proteoglycans such as lumican and fibromodulin is of importance, to be able to develop improved treatment for heart failure patients in the future. We used gene-modified mice to examine how lack of lumican or fibromodulin affected cardiac remodeling when mice were subjected to experimental cardiac pressure overload. We also performed in vitro overexpression experiments in cardiac cells. Cardiac levels of fibromodulin and lumican were increased in failing hearts. Our results show that even though fibromodulin and lumican are part of the same family of proteoglycans, they have contrasting effects in the failing heart. Mice lacking fibromodulin developed a mildly exacerbated hypertrophy during pressure overload, with no difference in mortality or fibrosis. Meanwhile, mice lacking lumican had high mortality and developed severe dilated heart failure with thin walls, impaired contraction and reduced fibrosis. In cultured cardiac fibroblasts, including human cells, fibromodulin reduced fibroblast migration and the expression of fibrosis-related proteins, suggesting an anti-fibrotic role. In cultured cardiac fibroblasts, lumican increased expression of fibrosis-related molecules including miR-21, suggesting a pro-fibrotic role. Our research contributes with insight into the molecular mechanisms underlying cardiac remodeling and failure