TY  - JOUR
AU  - Asare, Yaw
AU  - Yan, Guangyao
AU  - Schlegl, Christina
AU  - Prestel, Matthias
AU  - van der Vorst, Emiel P C
AU  - Teunissen, Abraham J P
AU  - Aronova, Arailym
AU  - Tosato, Federica
AU  - Naser, Nawraa
AU  - Caputo, Julio
AU  - Prevot, Geoffrey
AU  - Azzun, Anthony
AU  - Wefers, Benedikt
AU  - Wurst, Wolfgang
AU  - Schneider, Melanie
AU  - Forne, Ignasi
AU  - Bidzhekov, Kiril
AU  - Naumann, Ronald
AU  - van der Laan, Sander W
AU  - Brandhofer, Markus
AU  - Cao, Jiayu
AU  - Roth, Stefan
AU  - Malik, Rainer
AU  - Tiedt, Steffen
AU  - Mulder, Willem J M
AU  - Imhof, Axel
AU  - Liesz, Arthur
AU  - Weber, Christian
AU  - Bernhagen, Jürgen
AU  - Dichgans, Martin
TI  - A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis.
JO  - Immunity
VL  - 58
IS  - 3
SN  - 1074-7613
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-00423
SP  - 555 - 567.e9
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Atherosclerosis: genetics
KW  - Atherosclerosis: metabolism
KW  - Atherosclerosis: immunology
KW  - Histone Deacetylases: metabolism
KW  - Histone Deacetylases: genetics
KW  - Inflammasomes: metabolism
KW  - Humans
KW  - Mice
KW  - Inflammation: genetics
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: genetics
KW  - Repressor Proteins: metabolism
KW  - Repressor Proteins: genetics
KW  - Mice, Knockout
KW  - Regulatory Sequences, Nucleic Acid: genetics
KW  - Mice, Inbred C57BL
KW  - Plaque, Atherosclerotic: metabolism
KW  - Plaque, Atherosclerotic: genetics
KW  - Gene Expression Regulation
KW  - GWAS (Other)
KW  - HDAC9 (Other)
KW  - NLRP3 (Other)
KW  - atherosclerosis (Other)
KW  - cis-regulatory element (Other)
KW  - inflammasome (Other)
KW  - inflammation (Other)
KW  - nanobiologics (Other)
KW  - stroke (Other)
KW  - therapeutics (Other)
KW  - Histone Deacetylases (NLM Chemicals)
KW  - Inflammasomes (NLM Chemicals)
KW  - NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
KW  - HDAC9 protein, human (NLM Chemicals)
KW  - Hdac9 protein, mouse (NLM Chemicals)
KW  - Repressor Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39879983
DO  - DOI:10.1016/j.immuni.2025.01.003
UR  - https://pub.dzne.de/record/277527
ER  -