Histone deacetylases and atherosclerosis

描述（由申请人提供）：尽管降脂药物成功预防冠状动脉疾病和心肌梗死，但动脉粥样硬化仍然是西方世界和发展中国家疾病相关死亡的最常见原因。我们和其他人已经证明，组蛋白脱乙酰酶抑制剂（HDIs）具有抗炎作用，可用于治疗某些慢性炎症性疾病。鉴于动脉粥样硬化的炎症成分，并根据我们的初步数据，在这个建议中要测试的假设是，组蛋白脱乙酰酶9（HDAC 9）通过调节巨噬细胞中脂质稳态和炎症基因的表达在动脉粥样硬化的发病机制中起着重要作用。我们的长期目标是开发用于治疗和预防动脉粥样硬化的选择性HDIs。提出了三个具体目标。具体目标1将检验以下假设：巨噬细胞中HDAC 9的失活将减少，并且过表达将通过在体内修饰脂质稳态和炎症基因而增加Ldlr -/-小鼠中的动脉粥样硬化。我们将从HDAC 9缺陷小鼠和HDAC 9转基因小鼠向Ldlr-/-小鼠进行骨髓移植，并确定其对动脉粥样硬化的影响。具体目标2将检验HDAC 9通过调节巨噬细胞中的胆固醇流出和流入途径介导脂质稳态的假设。我们将使用巯基乙酸盐诱导的腹腔巨噬细胞或骨髓来源的巨噬细胞来研究不同水平的HDAC 9表达对胆固醇流出（ABCA 1、ABCG 1和SR-B1介导的）、胆固醇酯化以及脂蛋白结合和降解的影响。具体目标3将检验HDAC 9活性调节巨噬细胞中的炎症的假设。我们将使用表达不同量HDAC 9的巨噬细胞进行跨内皮迁移、趋化性和粘附测定。荧光或放射性标记的巨噬细胞将用于监测体内单核细胞-巨噬细胞归巢至动脉粥样硬化斑块。我们还将测量在IPS刺激后表达不同量的HDAC 9的巨噬细胞中的细胞因子、趋化因子、整合素和粘附分子。这项研究将为HDAC 9在动脉粥样硬化发病机制中发挥作用的机制提供新的见解。最终，这项研究可能为开发特异性组蛋白去乙酰化酶抑制剂提供基础，该抑制剂仅针对HDAC 9用于治疗人类动脉粥样硬化。

DESCRIPTION (provided by applicant): Despite the success of lipid lowering drugs for the prevention of coronary artery disease and myocardial infarction, atherosclerosis remains the most common cause of disease-related death in the Western world and in developing countries. We and others have demonstrated that histone deacetylase inhibitors (HDIs) have anti-inflammatory effects and can be used to treat certain chronic inflammatory diseases. Given the inflammatory component of atherosclerosis, and based on our preliminary data, the hypothesis to be tested in this proposal is that histone deacetylase 9 (HDAC9) plays an important role in the pathogenesis of atherosclerosis by regulating the expression of lipid homeostatic and inflammatory genes in macrophages. Our long term goal is to develop selective HDIs for the treatment and prevention of atherosclerosis. Three specific aims are proposed. Specific Aim 1 will test the hypothesis that inactivation of HDAC9 in macrophages will decrease, and overexpression will increase atherosclerosis in Ldlr -/- mice by modifying lipid homeostatic and inflammatory genes in vivo. We will do bone marrow transplant from HDAC9 deficient and HDAC9 transgenic mice to Ldlr-/- mice and determine its effect on atherosclerosis. The Specific Aim 2 will test the hypothesis that HDAC9 mediates lipid homeostasis by modulating cholesterol efflux and influx pathways in macrophages. We will use thioglyocollate-elicited peritoneal macrophages or bone marrow derived macrophages to study the effect of different levels of expression of HDAC9 on cholesterol efflux (ABCA1, ABCG1, and SR-B1 mediated), cholesterol esterification, and lipoprotein binding and degradation. Specific Aim 3 will test the hypothesis that HDAC9 activity regulates inflammation in macrophages. We will perform transendothelial migration, chemotaxis, and adhesion assays using macrophages expressing different amounts of HDAC9. Fluorescent or radiolabeled macrophages will be used to monitor monocyte- macrophage homing to atherosclerotic plaques in vivo. We will also measure cytokine, chemokines, integrins and adhesion molecules in macrophages expressing different amount of HDAC9 upon IPS stimulation. This study will provide new insight into the mechanisms by which HDAC9 plays a role in the pathogenesis of atherosclerosis. Ultimately, this study may provide the foundation for the development of specific histone deacetylase inhibitors that only targets HDAC9 for the treatment of atherosclerosis in humans.