PhD defense: Geir Florholmen

Gamle Festsal, Urbygningen, Karl Johansgt. 47, Tuesday May 23, 2006 at 10:15.

Cytokines and heart failure new roles for leukemia inhibitory factor in cardiomyocyte energy metabolism and contractile function.

Despite the best available treatment, heart failure is a major cause of morbidity in the Western societies. Several cytokine systems are activated in patients with heart failure and a major hypothesis is that that these molecules are involved in the development of the disease. It has therefore been important to identify these regulated cytokine systems and to define their effects on cells in the myocardium. A major aim of this thesis was therefore to identify effects of cytokine treatment on cardiomyocytes. This was performed by stimulating cardiomyocytes with the cytokines leukemia inhibitory factor and activin A, which both are upregulated in the failing myocardium.

We used isolated cardiomyocyte cultures as a model system. Cells were isolated from adult or neonatal Wistar rats and maintained in culture with or without cytokine treatment. Our experimental approach gave the opportunity to study how cardiomyocytes respond to cytokine stimulation.

This thesis has discovered novel effects of cytokine treatment on cardiomyocyte function. Cardiomyocytes respond to this treatment by regulating key biological processes. Our experiments revealed several effects of cytokine treatment. Chronic LIF treatment induced cell growth with organization of sarcomeric proteins, altered contractile function, reduced energy production and reduced the cellular response to insulin. The most important effect of activin A was inhibition of the LIF-induced organization of sarcomeric proteins. Several of the reported changes are also observed in failing hearts, supporting the hypothesis that leukemia inhibitory factor and possibly activin A participate in the development of the disease. Modulating the actions of these cytokines has therefore the potential to improve heart failure treatment. This emphasizes the importance of defining functional effects of cytokines on cells within the myocardium.

Florholmen, Geir











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