ORP4L Facilitates Macrophage Survival via G-Protein-Coupled Signaling: ORP4L-/- Mice Display a Reduction of Atherosclerosis.

Rationale: Macrophage survival within the arterial wall is a central factor contributing to atherogenesis. Oxysterols, major components of oxidized LDL (ox-LDL), exert cytotoxic effects on macrophages. Objective: To determine whether ORP4L, an oxysterol-binding protein, affects macrophage survival and the pathogenesis of atherosclerosis. Methods and Results: By hiring cell biological approaches and ORP4L-/- mice, we show that ORP4L co-expresses with and forms a complex with G&alphaq/11 and PLCβ3 in macrophages. ORP4L facilitates G protein-coupled ligand-induced PLCβ3 activation, IP3 production and Ca2+ release from the endoplasmic reticulum. Through this mechanism, ORP4L sustains anti-apoptotic Bcl-XL expression through Ca2+-mediated CREB transcriptional regulation, and thus protects macrophages from apoptosis. Excessive stimulation with the oxysterol 25-hydroxycholesterol disassembles the ORP4L/Gαq/11/PLCβ3 complexes, resulting in reduced PLCβ3 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/ox-LDL to protect macrophage from apoptosis, thus playing an important role in the development of atherosclerosis.