Epigenetic regulation of vascular endothelial genes and laminar flow atheroprotection

在美国，动脉粥样硬化是导致死亡和残疾的主要原因， 在全世界都有。动脉粥样硬化的病变具有不均匀的分布， 人体脉管系统动脉的平直区域暴露于稳定的层流血液中 流动（L-流动），并保护免受动脉粥样硬化，而区域的分叉和 弯曲的特征是血流紊乱（D流）， 动脉粥样硬化改变人体血管树的结构是不现实的， 如消除动脉弯曲或分叉;然而，如果我们完全 了解赋予L流动脉粥样硬化保护作用的信号通路，我们将能够 通过药理学或生物化学方法在动脉的D-流动区域产生动脉粥样硬化保护作用， 防止动脉粥样硬化的分子手段。因此，我们的中心目标是确定 信号分子在抗动脉粥样硬化程序的L流，并探讨是否 靶向这些分子可导致动脉D-流动区域的动脉粥样硬化保护。 在我们最近的初步研究中，我们发现了一个独特的表观遗传途径， 有助于内皮细胞基因转录程序的差异调节， 对动脉粥样硬化保护层流与动脉粥样硬化酮干扰流的反应。在 本研究将探讨H3 K27 me 3依赖的表观遗传机制， 潜在的L-流与D-流对内皮基因表达的影响， 使用细胞培养系统和动物模型的组合研究动脉粥样硬化。 我们提出的研究结果将揭示重要的和创新的分子 血液动力学力依赖性动脉粥样硬化形成的潜在机制， 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.