Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis
Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis
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DOI：
10.1194/jlr.m800105-jlr200
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发表时间：
2008-11-01
影响因子：
6.5
通讯作者：
Thewke, Douglas P.
中科院分区：
文献类型：
--
作者：
Freeman-Anderson, Natalie E.;Pickle, Theresa G.;Thewke, Douglas P.
巨噬细胞凋亡是动脉粥样硬化病理生理学的重要过程。氧化低密度脂蛋白（OxLDL）是病变的主要成分，可有效诱导巨噬细胞凋亡。大麻素受体 2 (CB2) 是主要的巨噬细胞大麻素受体，调节与持续动脉粥样硬化相关的多个巨噬细胞过程；然而，CB2 在巨噬细胞凋亡中的作用尚不清楚。为了确定 CB2 是否影响与动脉粥样硬化相关的巨噬细胞凋亡途径，我们检查了 CB2 缺乏对 OxLDL 诱导的巨噬细胞凋亡的影响。与 OxLDL 孵育后，对常驻腹膜巨噬细胞进行原位末端转移酶介导的 dUTP 缺口末端标记 (TUNEL) 分析，检测到凋亡的 CB2(-/-) 巨噬细胞明显少于 CB2(+/+) 巨噬细胞（27.9 +/- 6 4.7% vs. 61.9 +/- 6 8.5%，P < 0.001）或7-酮胆固醇 (7KC)（18.9 +/- 10.5% 对比 54.1 +/- 6.9%，P < 0.001），OxLDL 的氧甾醇成分。 Caspase-3 活性； procaspase-3 的蛋白水解转化；在 7KC 处理的 CB2(-/-) 巨噬细胞中，caspase-3 底物 PARP 的裂解也减少。此外，CB2(-/-) 巨噬细胞中促生存激酶 Akt 响应 7KC 的失活受到损害。这些结果表明，CB2 表达增加了巨噬细胞对 OxLDL 诱导的细胞凋亡的敏感性，部分是通过调节氧甾醇对 Akt 存活途径的影响，并且 CB2 可能通过调节病变巨噬细胞凋亡来影响动脉粥样硬化。
Macrophage apoptosis is an important process in the pathophysiology of atherosclerosis. Oxidized low-density lipoproteins (OxLDL) are a major component of lesions and potently induce macrophage apoptosis. Cannabinoid receptor 2 (CB2), the predominant macrophage cannabinoid receptor, modulates several macrophage processes associated with ongoing atherosclerosis; however, the role of CB2 in macrophage apoptosis is unknown. To determine if CB2 influences a macrophage apoptotic pathway relevant to atherosclerosis, we examined the effect of CB2 deficiency on OxLDL-induced macrophage apoptosis. In situ terminal transferase-mediated dUTP nick end labeling (TUNEL) analysis of resident peritoneal macrophages detected significantly fewer apoptotic CB2(-/-) macrophages than CB2(+/+) macrophages after incubation with OxLDL (27.9 +/- 6 4.7% vs. 61.9 +/- 6 8.5%, P < 0.001) or 7-ketocholesterol (7KC) (18.9 +/- 10.5% vs. 54.1 +/- 6.9%, P < 0.001), an oxysterol component of OxLDL. Caspase-3 activity; proteolytic conversion of procaspase-3; and cleavage of a caspase-3 substrate, PARP, were also diminished in 7KC-treated CB2(-/-) macrophages. Furthermore, the deactivation of the prosurvival kinase, Akt, in response to 7KC was impaired in CB2(-/-) macrophages. These results suggest that CB2 expression increases the susceptibility of macrophages to OxLDL-induced apoptosis, in part, by modulating the effect of oxysterols on the Akt survival pathway and that CB2 may influence atherosclerosis by modulating lesional macrophage apoptosis.