Regulation of laminar flow atheroprotective genes by HDAC5

描述(申请人提供)：动脉粥样硬化是美国人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特征。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会造成促炎环境，从而导致内皮功能障碍和动脉粥样硬化。动脉粥样硬化的病变在人体血管中的分布不均匀。动脉的直段暴露在稳定的层流血流中，并受到动脉粥样硬化的保护，而包含分叉和弯曲的区域的特点是血流紊乱，容易导致动脉粥样硬化病变的形成。本项目的总体目标是阐明层流动脉粥样硬化保护的本质，确定生理性层流抗动脉粥样硬化过程中的关键分子和信号通路。我们将进一步定义新的策略，以激活暴露在扰动血流中的动脉粥样硬化区域的动脉粥样硬化保护机制，以防止动脉粥样硬化。转录因子Kr？ppel-like factor2(KLF2)是一种整合多种内皮功能的重要动脉粥样硬化保护基因。尤其是，KLF2是一种层流反应基因，通过增强内皮型一氧化氮合酶(ENOS)的表达和活性，介导了层流的许多动脉粥样硬化保护作用，包括抑制白细胞与内皮的黏附，改善内皮功能障碍。然而，在内皮生物学中，层流与KLF2激活和生理功能之间的分子机制仍然很难理解。本实验室的新证据表明，组蛋白脱乙酰基酶5(HDAC5)是在动脉粥样硬化保护过程中促进KLF2 L流动激活的重要分子连接物。为了验证我们的假设，我们将在培养细胞和小鼠中结合生化、细胞生物学和遗传学方法来研究HDAC5在KLF2层流调节和动脉粥样硬化保护中的功能作用和分子机制。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具有指导意义，例如特别取消对KLF2的HDAC5抑制，以限制动脉粥样硬化。

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.