Epigenetic regulation of vascular endothelial genes and laminar flow atheroprotection

动脉粥样硬化是美国人死亡和残疾的主要原因， 在世界各地。动脉粥样硬化病变分布不均匀。 人类的血管系统。动脉的直段暴露在稳定的层流血液中。 血流(L-血流)并受到动脉粥样硬化的保护，而分叉处和 曲率的特征是血液流动紊乱(D-flow)，容易发生 动脉硬化。改变人类血管树的结构是不现实的 作为动脉弯曲或分叉的消除；然而，如果我们完全 了解了L-血流动脉粥样硬化保护的信号通路，我们就能够 通过药物或药物在动脉D-血流区域产生动脉粥样硬化保护作用 预防动脉粥样硬化形成的分子手段。因此，我们的中心目标是确定关键 信号分子在L抗动脉粥样硬化中的作用及机制探讨 以这些分子为靶点可能导致动脉D-血流区域的动脉粥样硬化保护。 在我们最近的初步研究中，我们发现了一条独特的表观遗传途径 有助于血管内皮细胞基因转录程序的差异调控 对抗动脉粥样硬化层流与受激扰动流的响应。在……里面 这一建议，我们将探索H3K27me3依赖的表观遗传机制 L-Flow与D-Flow对内皮细胞基因表达的影响 采用细胞培养系统和动物模型相结合的方法研究动脉粥样硬化。 我们提议的研究结果将揭示重要的和创新的分子 血流动力依赖的动脉粥样硬化形成的潜在机制，可能 确定治疗动脉粥样硬化性血管疾病的新治疗策略。

Atherosclerosis is the major cause of death and disability in the United States and throughout the world. The lesions of atherosclerosis have a non-uniform distribution in the human vasculature. Straight regions of arteries are exposed to steady laminar blood flow (L-flow) and are protected from atherosclerosis, whereas regions of bifurcations and curvatures are characterized by disturbed blood flow (D-flow) that are predisposed to atherosclerosis. It is unrealistic to alter the architecture of the human vascular tree such as elimination of the arterial curvature or bifurcation; however, if we completely understand the signaling pathways conferring L-flow atheroprotection, we will be able to produce the atheroprotective action in D-flow areas of arteries by pharmacological or molecular means to prevent atherogenesis. Thus, our central goal is to identify the key signaling molecules in the anti-atherogenic programs of L-flow and to explore whether targeting these molecules could lead to atheroprotection in the D-flow regions of arteries. In our recent preliminary studies we have uncovered a unique epigenetic pathway that contributes to differential regulation of endothelial gene transcription programs in response to the atheroprotective laminar flow versus the atheroprone disturbed flow. In this proposal, we will explore the H3K27me3-dependent epigenetic mechanisms underlying L-flow versus D-flow effects on endothelial gene expression and atherosclerosis using the combinations of cell culture systems and animal models. Results from our proposed studies will reveal important and innovative molecular mechanisms underlying the hemodynamic forces-dependent atherogenesis, which may identify new therapeutic strategies for the treatment of atherosclerotic vascular diseases.