Regulation of laminar flow atheroprotective genes by HDAC5

描述（由申请人提供）：动脉粥样硬化是美国死亡和残疾的主要原因。内皮功能障碍和炎症是动脉粥样硬化的标志。高血压、肥胖、糖尿病、吸烟、高脂血症和遗传易感性等危险因素产生了导致内皮功能障碍和动脉粥样硬化形成的促炎环境。动脉粥样硬化的病变在人体血管系统中具有不均匀的分布。动脉的直区域暴露于稳定的层流血流中，并被保护免于动脉粥样硬化，而包含分叉和弯曲的区域的特征在于使血管易于形成动脉粥样硬化病变的干扰血流。本课题的总体目标是阐明层流抗动脉粥样硬化的本质，确定生理层流抗动脉粥样硬化的关键分子和信号通路。我们将进一步确定新的策略，以激活动脉粥样硬化保护机制的动脉粥样硬化区暴露于干扰流，以防止动脉粥样硬化。转录因子Kr？ppel样因子2（KLF2）是整合多种内皮功能的关键动脉粥样硬化保护基因。特别是，KLF2是一个层流反应性基因，并介导层流的许多动脉粥样硬化保护作用，包括抑制白细胞粘附到内皮和改善内皮功能障碍，通过增强内皮一氧化氮合酶（eNOS）的表达和活性。然而，在内皮生物学中，连接层流与KLF2活化和生理功能的分子机制在很大程度上仍然难以捉摸。我们实验室出现的新证据表明，组蛋白脱乙酰酶5（HDAC 5）是一个重要的分子连接体，在动脉粥样硬化保护过程中促进KLF 2的L流激活。为了验证我们的假设，我们将在培养的细胞和小鼠中使用生物化学，细胞生物学和遗传学方法的组合来研究HDAC 5的功能作用和KLF 2的层流调节和动脉粥样硬化保护的分子机制。该项目的结果将提供对层流动脉粥样硬化保护机制的详细了解，并将对开发新的治疗方法产生影响，例如特异性去除KLF 2上的HDAC 5抑制，以限制动脉粥样硬化。 公共卫生相关性：在美国，动脉粥样硬化是死亡和残疾的主要原因。动脉粥样硬化病变在人体血管系统中呈局灶性分布，大直动脉内稳定的层流血流主要通过上调内皮细胞中的动脉粥样硬化保护基因来提供动脉粥样硬化保护功能。我们最近发现HDAC5，一个重要的转录抑制因子，参与层流介导的动脉粥样硬化保护基因的调节。这项拟议的研究将研究层流对HDAC 5的机械和分子机制，并开发新的方法来抑制HDAC 5，在传统的artheroprone血管系统中建立外源性动脉粥样硬化保护作用。该提案将显着增加我们对层流介导动脉粥样硬化保护机制的理解，从而为开发新的治疗方法以预防动脉粥样硬化提供基础。

DESCRIPTION (provided by applicant): Atherosclerosis is the major cause of death and disability in the United States. Endothelial dysfunction and inflammation are hallmarks of atherosclerosis. The risk factors such as hypertension, obesity, diabetes, smoking, hyperlipidemia, and genetic predisposition create a proinflammatory environment that leads to endothelial dysfunction and atherogenesis. The lesions of atherosclerosis have a non-uniform distribution in the human vasculature. Straight regions of arteries are exposed to steady laminar blood flow and are protected from atherosclerosis, whereas regions containing bifurcations and curvatures are characterized by disturbed blood flow that predisposes vessels to atherosclerotic lesion formation. The overall goals of this project are to elucidate the nature of laminar flow atheroprotection, identify the key molecules and signal pathways in the anti-atherogenic programs of physiological laminar flow. We will further define new strategies to activate the atheroprotective mechanism in the atheroprone regions of arteries exposed to disturbed flow to prevent atherosclerosis. The transcription factor Kr?ppel-like factor 2 (KLF2) has emerged as a key atheroprotective gene integrating multiple endothelial functions. In particular, KLF2 is a laminar flow responsive gene and mediates many atheroprotective effects of laminar flow including the inhibition of leukocyte adhesion to endothelium and the improvement of endothelial dysfunction through enhancing endothelial nitric oxide synthase (eNOS) expression and activity. However, the molecular mechanisms connecting laminar flow to KLF2 activation and physiological function in endothelial biology remain largely elusive. New evidence emerging from our laboratory suggests that histone deacetylase 5 (HDAC5) is a crucial molecular linker facilitating L-flow activation of KLF2 in the atheroprotective processes. To test our hypothesis, we will use a combination of biochemical, cell biological and genetic approaches in cultured cells and mice to examine the functional role of HDAC5 and molecular mechanisms in laminar flow regulation of KLF2 and atheroprotection. The results of this project will provide a detailed understanding of the mechanisms involved in laminar flow atheroprotection and will have implications for the development of new therapeutic approaches, such as specifically removing HDAC5 repression on KLF2, to limit atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause of death and disability in the United States. The lesions of atherosclerosis show a focal pattern of distribution in the human vasculature, and steady laminar blood flow within large straight arteries provides an atheroprotective function mainly through upregulation of the atheroprotective genes in endothelial cells. We have recently found that HDAC5, an important transcriptional repressor, is involved in laminar flow-mediated regulation of the atheroprotective genes. This proposed study will investigate mechanical and molecular mechanisms derived from laminar flow on HDAC5, and develop novel approaches to inhibit HDAC5, establishing exogenous atheroprotection in traditionally artheroprone vasculature. The proposal will significantly increase our understanding of mechanisms by which laminar flow mediates atheroprotection, and therefore provide the basis to develop new therapies to prevent atherosclerosis.