In normal myocardium multiple cell-cell junctions allow for close membrane apposition (via adherens junctions) that are very stable (via desmosomes) and support the formation of electrical junctions (gap junctions). The formation of this junctional triad is ideal for maintaining the normal function of cardiac tissue. A junctional type found in other systems, but lacking in normal myocardium is the tight junction (TJ), formed from a protein complex that includes isoforms of the Claudin proteins. These TJs provide a barrier function in many tissues, and increase extracellular resistance within tissues, which would have a negative impact in normal myocardium. This application focuses on mapping the formation of tight junctions in ischemic myocardium. We hypothesize that the release of cytokines, particularly Interleukin-1beta (IL-1beta) and Tumor Necrosis Factor alpha (TNFalpha) from myofibroblasts upregulate the tight junction- associated protein Claudin-1 at the transcriptional level. Studies in this application focus on mapping the timing of appearance of these junctions as well as determining which signaling pathways are involved in this novel protein upregulation following ischemia. We also propose to use sophisticated computer modeling to assess the impact on propagation that the addition of these extracellular barriers would provide.
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