Cytokine- and stress-induced myocardial hypertrophy

Myocardial hypertrophy can be induced through hormonal factors or stress-sensing molecules. Hence, it is necessary to study the activation and function of such hypertrophic mediators to completely understand the biological processes occurring during devel opment of heart failure. We will combine studies in several experimental heart failure models with studies of patient serum and failing cardiac tissue to identify novel cytokines as well as cytokine receptors causing hypertrophy and heart failure. In addi tion, we have identified the transmembrane protein syndecan-4 as a crucial signaling protein in development of hypertrophy. Syndecan-4 is a co-receptor for cytokine-mediated signaling and connects the extracellular matrix to the intracellular cytoskeleton , thus a putative stress-sensor. Hence, we propose a novel role for syndecan-4 as a key regulator of cytokine- and stress-induced cardiac hypertrophy. We will study how mechanical stimulation affects the ability of syndecan-4 to activate the calcineurin-N FAT pathway leading to cardiac hypertrophy. We also aim to identify cytokines which directly bind to the syndecan-4 molecule and investigate how these cytokines can interfere with or modulate syndecan-4 mediated hypertrophic signaling. Based on identified protein-protein interaction sites, we will develop novel peptides that specifically disrupt interactions between syndecan-4 and other proteins. Recently, we have successfully developed one such disruptor peptide that inhibits syndecan-4-calcineurin inter action and NFAT activation. We hypothesize that pathological hypertrophy in vivo may be blocked by inhibition of syndecan-4-mediated signaling. Preliminary experiments support this notion, as better preserved cardiac function after myocardial infarction w as observed in syndecan-4 knockout mice than in wild-type mice. Hence, syndecan-4 may be a new therapeutic target, and blocking of the syndecan-4 signaling pathway may be a novel approach to heart failure treatment.