Asare Yaw, Yan Guangyao, Schlegl Christina, Prestel Matthias, van der Vorst Emiel P C, Teunissen Abraham J P, Aronova Arailym, Tosato Federica, Naser Nawraa, Caputo Julio, Prevot Geoffrey, Azzun Anthony, Wefers Benedikt, Wurst Wolfgang, Schneider Melanie, Forne Ignasi, Bidzhekov Kiril, Naumann Ronald, van der Laan Sander W, Brandhofer Markus, Cao Jiayu, Roth Stefan, Malik Rainer, Tiedt Steffen, Mulder Willem J M, Imhof Axel, Liesz Arthur, Weber Christian, Bernhagen Jürgen, Dichgans Martin
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilian-University (LMU), Munich, Germany.
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilian-University (LMU), Munich, Germany.
Immunity. 2025 Mar 11;58(3):555-567.e9. doi: 10.1016/j.immuni.2025.01.003. Epub 2025 Jan 28.
Common genetic variants in a conserved cis-regulatory element (CRE) at histone deacetylase (HDAC)9 are a major risk factor for cardiovascular disease, including stroke and coronary artery disease. Given the consistency of this association and its proinflammatory properties, we examined the mechanisms whereby HDAC9 regulates vascular inflammation. HDAC9 bound and mediated deacetylation of NLRP3 in the NACHT and LRR domains leading to inflammasome activation and lytic cell death. Targeted deletion of the critical CRE in mice increased Hdac9 expression in myeloid cells to exacerbate inflammasome-dependent chronic inflammation. In human carotid endarterectomy samples, increased HDAC9 expression was associated with atheroprogression and clinical plaque instability. Incorporation of TMP195, a class IIa HDAC inhibitor, into lipoprotein-based nanoparticles to target HDAC9 at the site of myeloid-driven vascular inflammation stabilized atherosclerotic plaques, implying a lower risk of plaque rupture and cardiovascular events. Our findings link HDAC9 to atherogenic inflammation and provide a paradigm for anti-inflammatory therapeutics for atherosclerosis.
组蛋白去乙酰化酶（HDAC）9保守顺式调控元件（CRE）中的常见基因变异是包括中风和冠状动脉疾病在内的心血管疾病的主要危险因素。鉴于这种关联的一致性及其促炎特性，我们研究了HDAC9调节血管炎症的机制。HDAC9在NACHT和LRR结构域中与NLRP3结合并介导其去乙酰化，导致炎性小体激活和细胞溶解性死亡。在小鼠中靶向缺失关键的CRE会增加骨髓细胞中Hdac9的表达，从而加剧炎性小体依赖性慢性炎症。在人类颈动脉内膜切除术样本中，HDAC9表达增加与动脉粥样硬化进展和临床斑块不稳定性相关。将IIa类HDAC抑制剂TMP195掺入基于脂蛋白的纳米颗粒中，以在骨髓驱动的血管炎症部位靶向HDAC9，可稳定动脉粥样硬化斑块，这意味着斑块破裂和心血管事件的风险较低。我们的研究结果将HDAC9与动脉粥样硬化性炎症联系起来，并为动脉粥样硬化的抗炎治疗提供了范例。
