Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability
Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability
复制标题
DOI：
10.1161/circresaha.120.316743
复制
发表时间：
2020-08-28
影响因子：
20.1
通讯作者：
Dichgans, Martin
中科院分区：
文献类型：
--
作者：
Asare, Yaw;Campbell-James, Thomas A.;Dichgans, Martin
基本原理：表现为动脉粥样硬化的动脉炎症是全世界死亡的主要原因。全基因组关联研究已确定 HDAC（组蛋白脱乙酰酶）-9 在动脉粥样硬化及其临床并发症（包括中风和心肌梗塞）中发挥重要作用。 目的：确定 HDAC9 与这些血管病理学相关的机制，并探索其动脉粥样硬化保护的治疗潜力。 方法和结果：我们通过骨髓重建实验和小分子抑制剂的药理学靶向，研究了 HDAC9 对斑块易损性特征的影响。高脂血症小鼠。我们进一步使用 2 光子和活体显微镜来研究内皮激活和白细胞-内皮相互作用。我们发现造血Hdac9缺陷会减少病变巨噬细胞含量，同时增加纤维帽厚度，从而赋予斑块稳定性。我们证明 HDAC9 与 IKK（抑制性 kappa B 激酶）-alpha 和 beta 结合，导致它们脱乙酰化并随后激活，从而驱动巨噬细胞和内皮细胞的炎症反应。使用 IIa 类 HDAC 抑制剂 TMP195 对 HDAC9 进行药理学抑制，可通过减少内皮活化和白细胞募集以及限制巨噬细胞中的促炎反应来减弱病变形成。使用 RNA 测序进行的转录分析表明，TMP195 下调关键炎症途径，与 IKK β 的抑制作用一致。 TMP195 可以减缓已形成病变的进展并抑制炎症细胞的浸润。此外，TMP195 减少了斑块的脆弱性，从而增强了晚期病变中斑块的稳定性。对动脉粥样硬化患者的单核细胞进行离体治疗，可减少炎症细胞因子的产生，包括 IL（白细胞介素）-1 β 和 IL-6。 结论：我们的研究结果确定 HDAC9 是动脉粥样硬化斑块稳定性和 IKK 激活的调节因子，从而为 HDAC9 在全基因组关联研究中作为血管风险位点的重要性提供了机制解释。其治疗性抑制可能为减轻血管炎症提供有效的杠杆。
RATIONALE: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction.OBJECTIVE: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection.METHODS AND RESULTS: We studied the effects ofHdac9on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoieticHdac9deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-alpha and beta, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKK beta. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1 beta and IL-6.CONCLUSIONS: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation.