ORP4L Facilitates Macrophage Survival via G-Protein-Coupled Signaling: ORP4L-/- Mice Display a Reduction of Atherosclerosis.
Circ Res
; 119(12): 1296-1312, 2016 Dec 09.
Article
em En
| MEDLINE
| ID: mdl-27729467
ABSTRACT
RATIONALE Macrophage survival within the arterial wall is a central factor contributing to atherogenesis. Oxysterols, major components of oxidized low-density lipoprotein, exert cytotoxic effects on macrophages. OBJECTIVE:
To determine whether oxysterol-binding protein-related protein 4 L (ORP4L), an oxysterol-binding protein, affects macrophage survival and the pathogenesis of atherosclerosis. METHODS ANDRESULTS:
By hiring cell biological approaches and ORP4L-/- mice, we show that ORP4L coexpresses with and forms a complex with Gαq/11 and phospholipase C (PLC)-ß3 in macrophages. ORP4L facilitates G-protein-coupled ligand-induced PLCß3 activation, IP3 production, and Ca2+ release from the endoplasmic reticulum. Through this mechanism, ORP4L sustains antiapoptotic Bcl-XL expression through Ca2+-mediated c-AMP responsive element binding protein transcriptional regulation and thus protects macrophages from apoptosis. Excessive stimulation with the oxysterol 25-hydroxycholesterol disassembles the ORP4L/Gαq/11/PLCß3 complexes, resulting in reduced PLCß3 activity, IP3 production, and Ca2+ release, as well as decreased Bcl-XL expression and increased apoptosis. Overexpression of ORP4L counteracts these oxysterol-induced defects. Mice lacking ORP4L exhibit increased apoptosis of macrophages in atherosclerotic lesions and a reduced lesion size.CONCLUSIONS:
ORP4L is crucial for macrophage survival. It counteracts the cytotoxicity of oxysterols/oxidized low-density lipoprotein to protect macrophage from apoptosis, thus playing an important role in the development of atherosclerosis.Palavras-chave
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Receptores de Esteroides
/
Receptores Acoplados a Proteínas G
/
Aterosclerose
/
Macrófagos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2016
Tipo de documento:
Article