Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium
| Autor: | Maria-Jesus Sanz, Mireia López-Riera, Luisa Hueso, María Carmen Montesinos, Rebeca Ortega, Laura Piqueras, Mari Carmen Gomez-Cabrera, José T. Real |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Small interfering RNA Endothelium QH301-705.5 Receptors Cytoplasmic and Nuclear Vascular Cell Adhesion Molecule-1 Leukocyte Rolling Retinoid X receptor Article endothelial dysfunction Catalysis Inorganic Chemistry Mice Constitutive androstane receptor Cell Adhesion Human Umbilical Vein Endothelial Cells Leukocytes medicine Animals Humans Biology (General) Physical and Theoretical Chemistry Endothelial dysfunction QD1-999 Molecular Biology Spectroscopy constitutive androstane receptor Tumor Necrosis Factor-alpha Chemistry Organic Chemistry NF-kappa B Endothelial Cells leukocyte recruitment General Medicine medicine.disease Computer Science Applications Cell biology medicine.anatomical_structure Gene Expression Regulation Tumor necrosis factor alpha Intravital microscopy Signal Transduction |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 17 International Journal of Molecular Sciences, Vol 22, Iss 9267, p 9267 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22179267 |
| Popis: | 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, TNFα-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 TNFα 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 TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-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. |
| Databáze: | OpenAIRE |
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