Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium.
Por:
Lopez-Riera M, Ortega R, Hueso L, Montesinos M, Gomez-Cabrera M, Sanz M, Real J, Piqueras L
Publicada:
27 ago 2021
Ahead of Print:
27 ago 2021
Resumen:
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.
Filiaciones:
Lopez-Riera M:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Ortega R:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Hueso L:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Montesinos M:
Univ Valencia, Dept Pharmacol, Valencia 46010, Spain
Ctr Mol Recognit & Technol Dev IDM, Burjassot 46100, Spain
Gomez-Cabrera M:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Univ Valencia, Fac Med, Dept Physiol, Freshage Res Grp, Valencia 46010, Spain
Biomed Network Res Ctr Frailty & Hlth Aging CIBER, Madrid 28029, Spain
Sanz M:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Univ Valencia, Dept Pharmacol, Valencia 46010, Spain
Biomed Network Res Ctr Diabet & Associated Metab, Madrid 28029, Spain
Real J:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Univ Clin Hosp Valencia, Endocrinol & Nutr Serv, Valencia 46010, Spain
Biomed Network Res Ctr Diabet & Associated Metab, Madrid 28029, Spain
Piqueras L:
Inst Hlth Res INCLIVA, Valencia 46010, Spain
Univ Valencia, Dept Pharmacol, Valencia 46010, Spain
Biomed Network Res Ctr Diabet & Associated Metab, Madrid 28029, Spain
Green Accepted, gold
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