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Published on: June 30, 2016
Lysophosphatidic acid directly induces macrophage-derived foam cell formation by blocking the expression of SRBI
Linmu Chen1, Jun Zhang1, Xiao Deng1
1Institute of Life Science, Chongqing Medical University, Chongqing, 400016, PR China.
Insights
Lysophosphatidic acid (LPA) directly promotes foam cell formation in atherosclerosis by activating LPA1/3 receptors and the AKT pathway, leading to decreased Scavenger Receptor BI (SRBI) expression.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Cardiovascular disease, primarily atherosclerosis, is a major cause of death.
- Macrophage foam cell formation from oxidized LDL (ox-LDL) is key in early atherosclerotic lesions.
- Lysophosphatidic acid (LPA), found in ox-LDL, influences cardiovascular health.
Purpose of the Study:
- To investigate the direct effects of LPA on macrophage foam cell formation.
- To elucidate the molecular mechanisms underlying LPA-induced foam cell formation.
- To determine the role of LPA receptors and lipid transport proteins in this process.
Main Methods:
- Foam cell formation assessed using Oil red O staining and cholesterol quantitation in Raw264.7 cells.
- Western blot and RT-PCR used to analyze LPA receptors and lipid transport proteins.
- Pharmacological inhibitors (LPA1/3 antagonist, AKT inhibitor) employed to dissect signaling pathways.
Main Results:
- LPA significantly promoted foam cell formation in macrophages.
- LPA treatment decreased the expression of Scavenger Receptor BI (SRBI), a cholesterol efflux facilitator.
- Inhibition of LPA1/3 receptors or AKT pathway blocked LPA-induced foam cell formation and SRBI downregulation.
Conclusions:
- LPA directly drives foam cell formation, a critical step in atherosclerosis.
- The LPA1/3 receptor and AKT signaling pathway mediate LPA's effects.
- Downregulation of SRBI by LPA contributes to cholesterol accumulation in foam cells.
Abstract:
The leading cause of morbidity and mortality is the result of cardiovascular disease, mainly atherosclerosis. The formation of macrophage foam cells by ingesting ox-LDL and focal retention in the subendothelial space are the hallmarks of the early atherosclerotic lesion. Lysophosphatidic acid (LPA), which is a low-molecular weight lysophospholipid enriched in oxidized LDL, exerts a range of effects on the cardiovascular system. Previous reports show that LPA increases the uptake of ox-LDL to promote the formation of foam cells. However, as the most active component of ox-LDL, there is no report showing whether LPA directly affects foam cell formation. The aim of this study was to investigate the effects of LPA on foam cell formation, as well as to elucidate the underlying mechanism. Oil red O staining and a Cholesterol/cholesteryl ester quantitation assay were used to evaluate foam cell formation in Raw264.7 macrophage cells. We utilized a Western blot and RT-PCR to investigate the relationship between LPA receptors and lipid transport related proteins. We found that LPA promoted foam cell formation, using 200 μM for 24 h. Meanwhile, the expression of the Scavenger receptor BI (SRBI), which promotes the efflux of free cholesterol, was decreased. Furthermore, the LPA1/3 receptor antagonist Ki16425 significantly abolished the LPA effects, indicating that LPA1/3 was involved in the foam cell formation and SRBI expression induced by LPA. Additionally, the LPA-induced foam cell formation was blocked with an AKT inhibitor. Our results suggest that LPA-enhanced foam cell formation is mediated by LPA1/3 -AKT activation and subsequent SRBI expression.
