Role of 3beta-hydroxysteroid-delta 24 reductase in mediating antiinflammatory effects of high-density lipoproteins in endothelial cells.

McGrath, K C Y; Li, X H; Puranik, R; Liong, E C; Tan, J T M; Dy, V M; DiBartolo, B A; Barter, P J; Rye, K A; Heather, A K

McGrath, K C Y; Li, X H; Puranik, R; Liong, E C; Tan, J T M; Dy, V M; DiBartolo, B A; Barter, P J; Rye, K A; Heather, A K.

Afiliación

McGrath KC; Heart Research Institute, 114 Pyrmont Bridge Road, Camperdown, NSW, 2050, Australia.

Arterioscler Thromb Vasc Biol ; 29(6): 877-82, 2009 Jun.

Article en En | MEDLINE | ID: mdl-19325144

RESUMEN

OBJECTIVE: The purpose of this study was to investigate the ability of high-density lipoproteins (HDLs) to upregulate genes with the potential to protect against inflammation in endothelial cells. METHODS AND RESULTS: Human coronary artery endothelial cells (HCAECs) were exposed to reconstituted HDLs (rHDLs) for 16 hours before being activated with tumor necrosis factor-alpha (TNF-alpha) for 5 hours. rHDLs decreased vascular cell adhesion molecule-1 (VCAM-1) promoter activity by 75% (P<0.05), via the nuclear factor-kappa B (NF-kappaB) binding site. rHDLs suppressed the canonical NF-kappaB pathway and decreased many NF-kappaB target genes. Suppression of NF-kappaB and VCAM-1 expression by rHDLs or native HDLs was dependent on an increase in 3beta-hydroxysteroid-Delta 24 reductase (DHCR24) levels (P<0.05). The effect of HDLs on DHCR24 is dependent on SR-BI but not ABCAI or ABCGI. Silencing DHCR24 expression increased NF-kappaB (1.2-fold, P<0.05), VCAM-1 (30-fold, P<0.05), and NF-kappaB p50 (4-fold, P<0.05) and p65 subunits (150-fold, P<0.05). TNF-alpha activation of siDHCR24-treated cells increased expression of VCAM-1 (550-fold, P<0.001) and NF-kappaB (9-fold, P<0.001) that could no longer be suppressed by rHDLs. CONCLUSIONS: Results suggest that antiinflammatory effects of rHDLs are mediated partly through an upregulation of DHCR24. These findings raise the possibility of considering DHCR24 as a target for therapeutic modulation.

Asunto(s)

Apolipoproteína A-I/metabolismo; Arteritis/prevención & control; Aterosclerosis/prevención & control; Células Endoteliales/enzimología; Lipoproteínas HDL/metabolismo; Proteínas del Tejido Nervioso/metabolismo; Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo; Animales; Apolipoproteína A-I/administración & dosificación; Arteritis/enzimología; Arteritis/etiología; Arteritis/genética; Aterosclerosis/enzimología; Aterosclerosis/etiología; Aterosclerosis/genética; Células Cultivadas; Colesterol en la Dieta; Modelos Animales de Enfermedad; Perfilación de la Expresión Génica; Regulación de la Expresión Génica; Humanos; Quinasa I-kappa B/metabolismo; Proteínas I-kappa B/metabolismo; Infusiones Intravenosas; Lipoproteínas HDL/administración & dosificación; Inhibidor NF-kappaB alfa; FN-kappa B/metabolismo; Proteínas del Tejido Nervioso/genética; Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética; Regiones Promotoras Genéticas; Interferencia de ARN; ARN Interferente Pequeño/metabolismo; Conejos; Transfección; Factor de Necrosis Tumoral alfa/metabolismo; Molécula 1 de Adhesión Celular Vascular/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arteritis / Apolipoproteína A-I / Células Endoteliales / Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH / Aterosclerosis / Lipoproteínas HDL / Proteínas del Tejido Nervioso Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2009 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos

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