Endothelial dysfunction in cardiovascular diseases such as atherosclerosis and hypertension is an important factor contributing to the high morbidity of these conditions. The role of cytokines, such as tumor necrosis factor (TNF), play in regulating endothelial cell function and increasing the severity of these diseases is poorly understood. Recent evidence indicate that cytokine-stimulated synthesis of the vasoconstrictor peptide endothelin-1 contributes to the pathological changes.
The aim of this project is to identify the TNF receptor and signal transduction pathways responsible for TNFa-induced endothelin-l production in human endothelial cells. Specific TNF receptor neutralising antibodies and selective receptor depletion (by antisense technology) will be used to identify the receptor involved. TNF receptor signaling will be investigate using inhibitors of known signal transduction pathways, by studying TNFa-induced protein phosphorylation, and by identifying proteins which bind to the cytoplasmic domain of the TNF receptor. This work will yield new insights into regulating endothelial function in inflammation and cardiovascular diseases.