Journal Article

DZNE-2025-00423

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis.

Asare, Y. ; Yan, G. ; Schlegl, C. ; Prestel, M.Extern* ; van der Vorst, E. P. C. ; Teunissen, A. J. P. ; Aronova, A. ; Tosato, F. ; Naser, N. ; Caputo, J. ; Prevot, G. ; Azzun, A. ; Wefers, B.DZNE* ; Wurst, W.DZNE* ; Schneider, M. ; Forne, I. ; Bidzhekov, K. ; Naumann, R. ; van der Laan, S. W. ; Brandhofer, M. ; Cao, J. ; Roth, S. ; Malik, R. ; Tiedt, S. ; Mulder, W. J. M. ; Imhof, A. ; Liesz, A. ; Weber, C. ; Bernhagen, J. ; Dichgans, M. (Last author)DZNE*

2025
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.immuni.2025.01.003

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.

Keyword(s): Animals (MeSH) ; Atherosclerosis: genetics (MeSH) ; Atherosclerosis: metabolism (MeSH) ; Atherosclerosis: immunology (MeSH) ; Histone Deacetylases: metabolism (MeSH) ; Histone Deacetylases: genetics (MeSH) ; Inflammasomes: metabolism (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Inflammation: genetics (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: genetics (MeSH) ; Repressor Proteins: metabolism (MeSH) ; Repressor Proteins: genetics (MeSH) ; Mice, Knockout (MeSH) ; Regulatory Sequences, Nucleic Acid: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Plaque, Atherosclerotic: metabolism (MeSH) ; Plaque, Atherosclerotic: genetics (MeSH) ; Gene Expression Regulation (MeSH) ; GWAS ; HDAC9 ; NLRP3 ; atherosclerosis ; cis-regulatory element ; inflammasome ; inflammation ; nanobiologics ; stroke ; therapeutics ; Histone Deacetylases ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; HDAC9 protein, human ; Hdac9 protein, mouse ; Repressor Proteins

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Contributing Institute(s):

1. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
2. Genome Engineering (AG Wurst)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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