Deficiency of lncRNA MERRICAL abrogates macrophage chemotaxis and diabetes-associated atherosclerosis

Diabetes -associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr - ' - mice on a high -fat, high -sucrose -containing (HFSC) diet identifies a macrophage -...

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Detalles Bibliográficos
Autores: Chen, JS, Jamaiyar, A, Wu, WN, Hu, Y, Zhuang, RL, Sausen, G, Cheng, HS, Vaz, CD, Pérez-Cremades, D, Tzani, A, McCoy, MG, Assa, C, Eley, S, Randhawa, V, Lee, K, Plutzky, J, Hamburg, NM, Sabatine, MS, Feinberg, MW
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p19571
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/19571
Access Level:acceso abierto
Palabra clave:CP: Immunology
atherosclerosis
chemotaxis
diabetes
lncRNA
macrophages
Descripción
Sumario:Diabetes -associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr - ' - mice on a high -fat, high -sucrose -containing (HFSC) diet identifies a macrophage -enriched nuclear long noncoding RNA (lncRNA), MERRICAL (macrophage -enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICAL expression increases by 249% in intimal lesions during progression. lncRNAmRNA pair genomic mapping reveals that MERRICAL positively correlates with the chemokines Ccl3 and Ccl4. MERRICAL -deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICAL guides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICAL deficiency in HFSC diet -fed Ldlr - ' - mice reduces lesion formation by 74% in the aortic sinus and 86% in the descending aorta by inhibiting leukocyte recruitment into the aortic wall and pro -inflammatory responses. These findings unveil a regulatory mechanism whereby a macrophage -enriched lncRNA potently inhibits chemotactic responses, alleviating lesion progression in diabetes.

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