Thewke Douglas, Freeman-Anderson Natalie, Pickle Theresa, Netherland Courtney, Chilton Courtney
Department of Biochemistry and Molecular Biology, Quillen College of Medicine, East Tennessee State University, 807 University Parkway, Johnson City, TN 37614, USA.
Biochem Biophys Res Commun. 2009 Apr 3;381(2):181-6. doi: 10.1016/j.bbrc.2009.02.020. Epub 2009 Feb 11.
Oxysterol-induced macrophage apoptosis may have a role in atherosclerosis. Macrophages lacking the type 2 cannabinoid receptor (CB2) are partially resistant to apoptosis induced by 7-ketocholesterol (7KC). AM-251 and SR144528 are selective antagonists of CB1 and CB2 receptors, respectively. We observed that both compounds reduce 7KC-induced apoptosis in Raw 264.7 macrophages. As oxysterol-induced macrophage apoptosis requires acyl-coenzymeA:cholesterol acyltransferase (ACAT) activity, we tested their affects on ACAT activity. AM-251 and SR144528 both reduced cholesteryl ester synthesis in unstimulated and acetylated LDL-stimulated Raw 264.7 macrophages, CB2(+/+) and CB2(-/-) peritoneal macrophages, as well as in vitro, in mouse liver microsomes. Consistent with inhibition of ACAT, the development of foam cell characteristics in macrophages by treatment with acetylated LDL was reduced by both compounds. This work is the first evidence that AM-251 and SR144528 are inhibitors of ACAT and as a result, might have anti-atherosclerotic activities independent of their affect on cannabinoid signaling.
氧化甾醇诱导的巨噬细胞凋亡可能在动脉粥样硬化中起作用。缺乏2型大麻素受体（CB2）的巨噬细胞对7-酮胆固醇（7KC）诱导的凋亡具有部分抗性。AM-251和SR144528分别是CB1和CB2受体的选择性拮抗剂。我们观察到这两种化合物均可减少Raw 264.7巨噬细胞中7KC诱导的凋亡。由于氧化甾醇诱导的巨噬细胞凋亡需要酰基辅酶A：胆固醇酰基转移酶（ACAT）活性，我们测试了它们对ACAT活性的影响。AM-251和SR144528均可降低未刺激和乙酰化低密度脂蛋白刺激的Raw 264.7巨噬细胞、CB2(+/+)和CB2(-/-)腹膜巨噬细胞以及体外小鼠肝微粒体中的胆固醇酯合成。与ACAT的抑制作用一致，两种化合物均减少了用乙酰化低密度脂蛋白处理巨噬细胞后泡沫细胞特征的发展。这项工作首次证明AM-251和SR144528是ACAT的抑制剂，因此可能具有独立于其对大麻素信号传导影响的抗动脉粥样硬化活性。
