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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 11, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn344
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Role of Activated Endocannabinoid System in Regulation of Cellular Cholesterol Metabolism in Macrophages

Li-sheng Jiang1,2, Jun Pu2, Zhi-hua Han2, Liu-hua Hu2 and Ben He2,*

1 Department of Geriatrics, Ren Ji hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
2 Department of Cardiology, Ren Ji hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

* Corresponding author: Professor Ben He, Department of Cardiology, Ren Ji hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Tel: 8621-68383609; Fax: 8621-68383609 E-mail address: heben1025{at}126.com.

Aims: Evidence from recent studies suggests that the endocannabinoid system participates in the regulation of lipid metabolism and body composition. We hypothesize that the system is activated by oxidized low-density lipoprotein (oxLDL) and regulates cellular cholesterol metabolism in macrophages.

Methods and Results: Primary peritoneal macrophages isolated from Sprague-Dawley rats and RAW264.7 mice macrophages were cultured. A liquid chromatography/mass spectrometry (LC/MS) system was used to measure the endocannabinoid anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cellular cholesterol levels in macrophages. The regulatory mechanisms of cellular cholesterol metabolism were also investigated by molecular biology methods. The results showed that the endocannabinoid system in macrophages was activated by oxLDL through elevation of the AEA and 2-AG levels and the up-regulation of the cannabinoid CB1 and CB2 receptor expression. Win55,212-2, a synthetic cannabinoid, promotes cellular cholesterol accumulation in macrophages, which was associated with an increase in the expression of CD36 and a decrease in the expression of ATP-binding cassette protein A1 (ABCA1) as mediated by an up-regulated peroxisome proliferator-activated receptor gamma (PPAR{gamma}). AM251, a selective cannabinoid CB1 receptor antagonist, impaired the abilities of Win55,212-2-treated macrophages to accumulate cholesterol by down-regulating CD36 receptor expression and up-regulating ABCA1 expression.

Conclusion: We have demonstrated, for the first time, that the endocannabinoid system in macrophages is activated by oxLDL and that the activated endocannabinoid system promotes cellular cholesterol accumulation in macrophages. The results also indicate that selectively blocking the CB1 receptor can reduce oxLDL accumulation in macrophages, which might represent a promising therapeutic strategy for atherosclerosis.

Time for primary review: 29 Days


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