Vascular endothelial cells (EC) become dysfunctional during the early stages of arteriosclerosis, expressing more proarteriogenic mediators and releasing fewer protective factors such as nitric oxide (NO). Endothelial dysfunction associated with the disease process or induced by exposing ECs to minimally modified lipoprotein (MM-LDL) is caused by a selective impairment in the Gi2-protein-dependent signal transduction pathway. Impaired signalling of the Gi2-protein results in a cyclic AMP-dependent activation of the transcription factor, NF-Kappa-beta leading to increased expression of adhesion molecules, procoagulant mediators, and chemotactic and mitogenic signals for smooth muscle cells and monocytes. In preliminary experiments, 17beta-estradiol inhibited the activation of NF-kappa/beta MM-LDL, LPS or TNF-alpha in human endothelial cells. Estrogen also increased mRNA levels of the NF-kappa-beta inhibitory protein Ikappa/beta-alpha. We hypothesize that female sex hormones will protect ECs from dysfunction by inhibiting the activation of NF-kappa beta. Molecular and biochemical assays will be performed in cultured human aortic endothelial cells to investigate the roles of the Gi- 2protein, reactive oxygen species, NO, I-kappa/beta, the estrogen receptor, and direct hormone receptor/NF-kappa/beta binding, in mediating the inhibition of NF-kappa/beta by female sex hormones.
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