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Lab Invest. 2019 Mar;99(3):421-437. doi: 10.1038/s41374-018-0151-3. Epub 2019 Jan 21.

OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells.

Author information

1
Departamento de Ciencias Biologicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Ave. Republica 239, 8370134, Santiago, Chile.
2
Millennium Institute on Immunology and Immunotherapy, Ave. Alameda 340, 8331150, Santiago, Chile.
3
Facultad de Medicina, Universidad de Atacama, Copayapu 485, 1531772, Copiapo, Chile.
4
Escuela de Química y Farmacia, Facultad de Ingeniería, Ciencia y Tecnología, Universidad Bernardo OHiggins, Viel 1497, 8370993, Santiago, Chile.
5
Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile.
6
Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Chile, Santiago, Chile.
7
Departamento de Ciencias Biologicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Ave. Republica 239, 8370134, Santiago, Chile. fsimon@unab.cl.
8
Millennium Institute on Immunology and Immunotherapy, Ave. Alameda 340, 8331150, Santiago, Chile. fsimon@unab.cl.

Abstract

Systemic inflammatory diseases enhance circulating oxidative stress levels, which results in the oxidation of circulating high-density lipoprotein (oxHDL). Endothelial cell function can be negatively impacted by oxHDL, but the underlying mechanisms for this remain unclear. Some reports indicate that the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is also a receptor for oxHDL. However, it is unknown if oxHDL induces increased LOX-1 expression at the plasma membrane, as an event that supports endothelial dysfunction. Therefore, the aims of this study were to determine if oxHDL induces plasma-membrane level changes in LOX-1 and, if so, to describe the underlying mechanisms in endothelial cells. Our results demonstrate that the incubation of arterial or vein endothelial cells with oxHDL (and not HDL) induces the increase of LOX-1 expression at the plasma membrane; effect prevented by LOX-1 inhibition. Importantly, same results were observed in endothelial cells from oxHDL-treated rats. Furthermore, the observed oxHDL-induced LOX-1 expression is abolished by the down-regulation of NOX-2 expression with siRNA (and no others NOX isoforms), by the pharmacological inhibition of NAD(P)H oxidase (with DPI or apocynin) or by the inhibition of NF-κB transcription factor. Coherently, LOX-1 expression is augmented by the incubation of endothelial cells with H2O2 or GSSG even in absence of oxHDL, indicating that the NOX-2/ROS/ NF-κB axis is involved. Interestingly, oxHDL incubation also increases TNF-α expression, cytokine that induces LOX-1 expression. Thus, our results suggest a positive feedback mechanism for LOX-1 receptor during inflammatory condition where an oxidative burst will generate oxHDL from native HDL, activating LOX-1 receptor which in turn will increase the expression of NOX-2, TNF-α and LOX-1 receptor at the plasma membrane. In conclusion, oxHDL-induced translocation of LOX-1 to the plasma membrane could constitute an induction mechanism of endothelial dysfunction in systemic inflammatory diseases.

PMID:
30664710
DOI:
10.1038/s41374-018-0151-3

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