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.
We recently found increased chymase expression in maternal vessel endothelium in PE. Chymase is a unique serine protease and a key mediator in cardiovascular and inflammatory cell signaling. It is a major ACE-independent angiotensin II converting enzyme in the cardiovascular tissues. However, how chymase is upregulated in PE is not known. In this study, we will investigate the molecular mechanisms of chymase activation and test our central hypothesis that aberrant posttranslational histone modification leads to chymase activation, subsequently results in endothelial activation/dysfunction in PE. The proposed studies will provide new insights into epigenetic regulation that link placenta activity with chymase upregulation and endothelial dysfunction in PE. Results from the proposed studies will not only provide a comprehensive understanding of chymase activation and its consequence on endothelial functionality in pregnancy, but also the new insights of CLP/chymase role in the pathophysiology and pathogenesis of vascular dysfunction in PE. This study has immediate translational potential and will provide a rationale for developing a new therapeutic platform to treat chymase activation associated with vascular diseases and metabolic disorders.
