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000277527 0247_ $$2doi$$a10.1016/j.immuni.2025.01.003
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000277527 037__ $$aDZNE-2025-00423
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000277527 1001_ $$aAsare, Yaw$$b0
000277527 245__ $$aA cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis.
000277527 260__ $$a[Cambridge, Mass.]$$bCell Press$$c2025
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000277527 520__ $$aCommon 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.
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000277527 650_7 $$2Other$$aGWAS
000277527 650_7 $$2Other$$aHDAC9
000277527 650_7 $$2Other$$aNLRP3
000277527 650_7 $$2Other$$aatherosclerosis
000277527 650_7 $$2Other$$acis-regulatory element
000277527 650_7 $$2Other$$ainflammasome
000277527 650_7 $$2Other$$ainflammation
000277527 650_7 $$2Other$$ananobiologics
000277527 650_7 $$2Other$$astroke
000277527 650_7 $$2Other$$atherapeutics
000277527 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHistone Deacetylases
000277527 650_7 $$2NLM Chemicals$$aInflammasomes
000277527 650_7 $$2NLM Chemicals$$aNLR Family, Pyrin Domain-Containing 3 Protein
000277527 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHDAC9 protein, human
000277527 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHdac9 protein, mouse
000277527 650_7 $$2NLM Chemicals$$aRepressor Proteins
000277527 650_2 $$2MeSH$$aAnimals
000277527 650_2 $$2MeSH$$aAtherosclerosis: genetics
000277527 650_2 $$2MeSH$$aAtherosclerosis: metabolism
000277527 650_2 $$2MeSH$$aAtherosclerosis: immunology
000277527 650_2 $$2MeSH$$aHistone Deacetylases: metabolism
000277527 650_2 $$2MeSH$$aHistone Deacetylases: genetics
000277527 650_2 $$2MeSH$$aInflammasomes: metabolism
000277527 650_2 $$2MeSH$$aHumans
000277527 650_2 $$2MeSH$$aMice
000277527 650_2 $$2MeSH$$aInflammation: genetics
000277527 650_2 $$2MeSH$$aNLR Family, Pyrin Domain-Containing 3 Protein: metabolism
000277527 650_2 $$2MeSH$$aNLR Family, Pyrin Domain-Containing 3 Protein: genetics
000277527 650_2 $$2MeSH$$aRepressor Proteins: metabolism
000277527 650_2 $$2MeSH$$aRepressor Proteins: genetics
000277527 650_2 $$2MeSH$$aMice, Knockout
000277527 650_2 $$2MeSH$$aRegulatory Sequences, Nucleic Acid: genetics
000277527 650_2 $$2MeSH$$aMice, Inbred C57BL
000277527 650_2 $$2MeSH$$aPlaque, Atherosclerotic: metabolism
000277527 650_2 $$2MeSH$$aPlaque, Atherosclerotic: genetics
000277527 650_2 $$2MeSH$$aGene Expression Regulation
000277527 7001_ $$aYan, Guangyao$$b1
000277527 7001_ $$aSchlegl, Christina$$b2
000277527 7001_ $$0P:(DE-2719)9001400$$aPrestel, Matthias$$b3$$udzne
000277527 7001_ $$avan der Vorst, Emiel P C$$b4
000277527 7001_ $$aTeunissen, Abraham J P$$b5
000277527 7001_ $$aAronova, Arailym$$b6
000277527 7001_ $$aTosato, Federica$$b7
000277527 7001_ $$aNaser, Nawraa$$b8
000277527 7001_ $$aCaputo, Julio$$b9
000277527 7001_ $$aPrevot, Geoffrey$$b10
000277527 7001_ $$aAzzun, Anthony$$b11
000277527 7001_ $$0P:(DE-2719)2810988$$aWefers, Benedikt$$b12$$udzne
000277527 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b13$$udzne
000277527 7001_ $$aSchneider, Melanie$$b14
000277527 7001_ $$aForne, Ignasi$$b15
000277527 7001_ $$aBidzhekov, Kiril$$b16
000277527 7001_ $$aNaumann, Ronald$$b17
000277527 7001_ $$avan der Laan, Sander W$$b18
000277527 7001_ $$aBrandhofer, Markus$$b19
000277527 7001_ $$aCao, Jiayu$$b20
000277527 7001_ $$aRoth, Stefan$$b21
000277527 7001_ $$aMalik, Rainer$$b22
000277527 7001_ $$aTiedt, Steffen$$b23
000277527 7001_ $$aMulder, Willem J M$$b24
000277527 7001_ $$aImhof, Axel$$b25
000277527 7001_ $$aLiesz, Arthur$$b26
000277527 7001_ $$aWeber, Christian$$b27
000277527 7001_ $$aBernhagen, Jürgen$$b28
000277527 7001_ $$0P:(DE-2719)2000030$$aDichgans, Martin$$b29$$eLast author$$udzne
000277527 773__ $$0PERI:(DE-600)2001966-X$$a10.1016/j.immuni.2025.01.003$$gVol. 58, no. 3, p. 555 - 567.e9$$n3$$p555 - 567.e9$$tImmunity$$v58$$x1074-7613$$y2025
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