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  3. Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium.

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium.

Fecha de publicación: Fecha Ahead of Print:

Autores de INCLIVA

Participantes ajenos a INCLIVA

  • Montesinos, MC

Grupos y Plataformas de I+D+i

Abstract

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFa-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFa induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFa-induced p38-MAPK/NF-?B activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFa-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.

Datos de la publicación

ISSN/ISSNe:
1661-6596, 1422-0067

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES  MDPI AG

Tipo:
Article
Páginas:
-
PubMed:
34502180

Citas Recibidas en Web of Science: 6

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Filiaciones mostrar / ocultar

Keywords

  • constitutive androstane receptor; endothelial dysfunction; leukocyte recruitment

Campos de Estudio

Financiación

CONSELLERIA DE SANIDAD (2019/200C)
CONSELLERIA EDUCACION/INNOVACION,UNIVERSIDADES, CIENCIA Y SOCIEDAD DIGITAL/EMPLEO (AICO/2019/250)
INSTITUTO SALUD CARLOS III (PI18/00209)
MINISTERIO ECONOMIA Y COMPETITIVIDAD (SAF2017-89714-R)

Proyectos y Estudios Clínicos

RETOS 2017. MODULACION FARMACOLOGICA DEL SISTEMA INMUNE COMO DIANA CLAVE EN LA PREVENCION DE LA ENFERMEDAD CARDIOVASCULAR ASOCIADA A DESORDENES METABOLICOS. SINTESIS DE FARMACOS NOVEDOSOS

Investigador Principal: MARIA JESUS SANZ FERRANDO

SAF2017-89714-R . MINISTERIO ECONOMIA Y COMPETITIVIDAD . 2018

Identificación de nuevos mecanismos implicados en la angiogénesis e inflamación en pacientes obesos. Modulación por ligandos de receptores nucleares constitutivos de androstano.

Investigador Principal: JOSE TOMAS REAL COLLADO

PI18/00209 . INSTITUTO SALUD CARLOS III . 2019

Efecto de la cirugía bariátrica en la inflamación vascular en pacientes con obesidad morbida y diabéticos.

Investigador Principal: LAURA PIQUERAS RUIZ

AICO/2019/250 . CONSELLERIA EDUCACION/INNOVACION,UNIVERSIDADES, CIENCIA Y SOCIEDAD DIGITAL/EMPLEO . 2019

CDEI-04/20-A GENT LAURA PIQUERAS (2019/200) CONTRATO

Investigador Principal: LAURA PIQUERAS RUIZ

2019/200C . CONSELLERIA DE SANIDAD

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