Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Circ Res ; 127(6): 811-823, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32546048

RESUMO

RATIONALE: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction. OBJECTIVE: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. METHODS AND RESULTS: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and ß, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKß. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1ß and IL-6. CONCLUSIONS: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.


Assuntos
Artérias/enzimologia , Aterosclerose/enzimologia , Histona Desacetilases/metabolismo , Quinase I-kappa B/metabolismo , Placa Aterosclerótica , Proteínas Repressoras/metabolismo , Acetilação , Idoso , Idoso de 80 Anos ou mais , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/patologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Ativação Enzimática , Feminino , Fibrose , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Humanos , Quinase I-kappa B/genética , Mediadores da Inflamação/metabolismo , Migração e Rolagem de Leucócitos , Macrófagos/enzimologia , Macrófagos/patologia , Masculino , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Monócitos/enzimologia , Monócitos/patologia , Ligação Proteica , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...