Mechanism of chymase activation in endothelial cells

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DESCRIPTION (provided by applicant): The objective of this study is to explore the mechanism of increased chymase expression in endothelial cells (ECs) and to test our hypothesis that histone modification leads to chymase activation in vascular ECs in preeclampsia (PE). Chymase, a chymotrypsin-like serine protease (CLP), is a significant contributor to cardiovascular diseases, including hypertension and diabetes. Chymase is an ACE-independent angiotensin II (Ang II) converting enzyme. Ang II, a potent vasoconstrictor, plays a key role in increased vasoconstriction in PE. Chymase expression is increased in maternal vessel endothelium in women with PE compared to normotensive controls. CLP/chymase derived from PE placenta is not only responsible for triggering EC chymase activation, but also contributes to placental sFlt-1 release in PE. However, the mechanism that underlies chymase activation remains elusive. To explore the mechanism of EC chymase activation in PE, in our preliminary study that using an in vitro model system that mimics the increased EC chymase expression in PE, we found that specific HDAC inhibition directly contributes to chymase regulation. In this study, we propose for the first time to explore the epigenetic basis of placenta-mediated activation of chymase in the endothelium, specifically, we will test the hypothesis that aberrant epigenetic regulation (histone modification) mediated endothelial chymase activation in PE. This hypothesis will be tested in 2 specific aims. Aim 1 will demonstrate how placental factor-mediated histone modification leads to endothelial chymase expression in PE and Aim 2 will demonstrate how histone acetylation leads to chymase activation in ECs. Using state-of-the-art techniques, chymase gene transfer approach, siRNA and specific inhibitors and blockers of target molecules, we will define how histone modification mediates chymase expression in EC in PE. These studies represent the first attempt to investigate the role of epigenetic regulation, which connects placenta dysfunction, chymase activation, and EC phenotypic changes that occur in PE. Results obtained from this study will lead to novel mechanistic explanation of chymase activation and its pathological effects on endothelial function in PE and will provide rationale for developing a new therapeutic strategy to treat chymase activation associated vascular diseases and metabolic disorders.