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, 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.
Highlights
With the aim of identifying more effective strategies to treat and prevent endothelial dysfunction associated with pathologies such as atherosclerosis, and co-morbid metabolic disorders characterized by endothelial dysfunction, we evaluate the effect of constitutive androstane receptor (CAR)
CAR expression was analyzed in human umbilical vein endothelial cells (HUVEC)
Given that TNFα stimulation of endothelial cells can trigger the release of different chemokines that contribute to leukocyte arrest, we evaluated the effect of CAR agonist in TNFα-induced MCP-1/CCL2 and RANTES/CCL5 release from human endothelial cells
Summary
Atherosclerosis involves an inflammatory response, consisting of intimal accumulation of leukocytes and lipid-laden macrophages throughout the entire atherogenic process [1,2]. Endothelial dysfunction, one of the earliest stages of atherogenesis, leads to a prothrombotic and proinflammatory phenotype of the endothelium which induces leukocyte attachment and subsequent migration [3]. Expression of diverse cell adhesion molecules and secretion of several proinflammatory cytokines and chemokines by immune and endothelial cells contribute to the leukocyte infiltration process [4,5]. CAR was described as a xenosensor that mediates xenobiotic drug-induced changes by increasing transcription of genes involved in drug clearance and disposition; later studies demonstrated an alternative role for CAR in regulating hormone levels in response to metabolic and nutritional stress [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
