Journal
CIRCULATION RESEARCH
Volume 119, Issue 12, Pages 1296-1312Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.116.309603
Keywords
apoptosis; atherosclerosis; bcl-XL protein; macrophages; oxidized low density lipoprotein
Funding
- Fundamental Research Funds for the Central Universities
- National Basic Research Program of China [2012CB517502]
- Academy of Finland [285223]
- Sigrid Juselius Foundation
- Finnish Foundation for Cardiovascular Research
- Magnus Ehrnrooth Foundation
- National Natural Science Foundation of China [81325001, 91439122]
- Novo Nordisk Fonden [NNF11OC1014724] Funding Source: researchfish
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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 and Results: By hiring cell biological approaches and ORP4L(-/-) mice, we show that ORP4L coexpresses with and forms a complex with G alpha(q/11) and phospholipase C (PLC)-beta 3 in macrophages. ORP4L facilitates G-protein-coupled ligand-induced PLC beta 3 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/G alpha(q/11)/PLC beta 3 complexes, resulting in reduced PLC beta 3 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.
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