Histone deacetylases and atherosclerosis

描述（由申请人提供）：尽管降脂药物在预防冠状动脉疾病和心肌梗死方面取得了成功，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去乙酰化酶抑制剂（hdi）具有抗炎作用，可用于治疗某些慢性炎症性疾病。考虑到动脉粥样硬化的炎症成分，根据我们的初步数据，本提案需要验证的假设是，组蛋白去乙酰化酶9 （HDAC9）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过程中发挥重要作用。我们的长期目标是开发选择性hdi来治疗和预防动脉粥样硬化。提出了三个具体目标。特异性Aim 1将通过在体内改变脂质稳态和炎症基因，验证巨噬细胞中HDAC9失活减少，过表达会增加Ldlr -/-小鼠动脉粥样硬化的假设。我们将把HDAC9缺陷小鼠和HDAC9转基因小鼠的骨髓移植到Ldlr-/-小鼠身上，并确定其对动脉粥样硬化的影响。特异性目的2将验证HDAC9通过调节巨噬细胞胆固醇外排和内流途径介导脂质稳态的假设。我们将使用巯基果胶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HDAC9表达对胆固醇外流（ABCA1、ABCG1和SR-B1介导）、胆固醇酯化和脂蛋白结合和降解的影响。特异性Aim 3将验证HDAC9活性调节巨噬细胞炎症的假设。我们将使用表达不同量HDAC9的巨噬细胞进行跨内皮迁移、趋化和粘附试验。荧光或放射标记的巨噬细胞将用于监测单核细胞-巨噬细胞在体内归巢到动脉粥样硬化斑块。我们还将测量IPS刺激下表达不同量HDAC9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HDAC9在动脉粥样硬化发病机制中的作用提供新的见解。最终，该研究可能为开发仅针对HDAC9的特异性组蛋白去乙酰化酶抑制剂治疗人类动脉粥样硬化提供基础。

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.