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@ARTICLE{Asare:277527,
author = {Asare, Yaw and Yan, Guangyao and Schlegl, Christina and
Prestel, Matthias and van der Vorst, Emiel P C and
Teunissen, Abraham J P and Aronova, Arailym and Tosato,
Federica and Naser, Nawraa and Caputo, Julio and Prevot,
Geoffrey and Azzun, Anthony and Wefers, Benedikt and Wurst,
Wolfgang and Schneider, Melanie and Forne, Ignasi and
Bidzhekov, Kiril and Naumann, Ronald and van der Laan,
Sander W and Brandhofer, Markus and Cao, Jiayu and Roth,
Stefan and Malik, Rainer and Tiedt, Steffen and Mulder,
Willem J M and Imhof, Axel and Liesz, Arthur and Weber,
Christian and Bernhagen, Jürgen and Dichgans, Martin},
title = {{A} cis-regulatory element controls expression of histone
deacetylase 9 to fine-tune inflammasome-dependent chronic
inflammation in atherosclerosis.},
journal = {Immunity},
volume = {58},
number = {3},
issn = {1074-7613},
address = {[Cambridge, Mass.]},
publisher = {Cell Press},
reportid = {DZNE-2025-00423},
pages = {555 - 567.e9},
year = {2025},
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.},
keywords = {Animals / Atherosclerosis: genetics / Atherosclerosis:
metabolism / Atherosclerosis: immunology / Histone
Deacetylases: metabolism / Histone Deacetylases: genetics /
Inflammasomes: metabolism / Humans / Mice / Inflammation:
genetics / NLR Family, Pyrin Domain-Containing 3 Protein:
metabolism / NLR Family, Pyrin Domain-Containing 3 Protein:
genetics / Repressor Proteins: metabolism / Repressor
Proteins: genetics / Mice, Knockout / Regulatory Sequences,
Nucleic Acid: genetics / Mice, Inbred C57BL / Plaque,
Atherosclerotic: metabolism / Plaque, Atherosclerotic:
genetics / Gene Expression Regulation / GWAS (Other) / HDAC9
(Other) / NLRP3 (Other) / atherosclerosis (Other) /
cis-regulatory element (Other) / inflammasome (Other) /
inflammation (Other) / nanobiologics (Other) / stroke
(Other) / therapeutics (Other) / Histone Deacetylases (NLM
Chemicals) / Inflammasomes (NLM Chemicals) / NLR Family,
Pyrin Domain-Containing 3 Protein (NLM Chemicals) / HDAC9
protein, human (NLM Chemicals) / Hdac9 protein, mouse (NLM
Chemicals) / Repressor Proteins (NLM Chemicals)},
cin = {AG Dichgans / AG Wurst},
ddc = {610},
cid = {I:(DE-2719)5000022 / I:(DE-2719)1140001},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39879983},
doi = {10.1016/j.immuni.2025.01.003},
url = {https://pub.dzne.de/record/277527},
}