A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis

Asare, Yaw ; Yan, Guangyao; Schlegl, Christina; Prestel, Matthias; Vorst, Emiel P.C. van der; 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; Laan, Sander W. van der ; Brandhofer, Markus; Cao, Jiayu; Roth, Stefan; Malik, Rainer; Tiedt, Steffen; Mulder, Willem J.M.; Imhof, Axel; Liesz, Arthur ; Weber, Christian ; Bernhagen, Jürgen und Dichgans, Martin (2025): A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis. In: Immunity, Bd. 58, Nr. 3: S. 555-567

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Institut für Schlaganfall- und Demenzforschung (ISD) ; Medizin > Klinikum der LMU München
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1074-7613
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198