Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice.
Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice.
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DOI：
10.1016/j.atherosclerosis.2010.07.060
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发表时间：
2010-11
期刊：
影响因子：
5.3
通讯作者：
Thewke, Douglas P.
中科院分区：
文献类型：
--
作者：
Netherland, Courtney D.;Pickle, Theresa G.;Bales, Alicia;Thewke, Douglas P.
关键词：
为了确定大麻素受体2（CB 2）是否在动脉粥样硬化中发挥作用，我们研究了全身性CB 2基因缺失对低密度脂蛋白受体缺陷（Ldlr−/−）小鼠高血压诱导的动脉粥样硬化形成的影响。Ldlr−/−和CB 2/Ldlr双基因敲除（CB 2 −/−Ldlr−/−）小鼠分别喂食致动脉粥样硬化饮食8周和12周。形态学分析显示，在致动脉粥样硬化饮食8周或12周后，Ldlr−/−和CB 2 −/−Ldlr−/−小鼠近端动脉粥样硬化病变面积之间没有显著差异。免疫组织化学染色显示，8周后Ldlr−/−和CB 2 −/−Ldlr−/−病变之间的巨噬细胞和平滑肌细胞（SMC）含量无显著差异。然而，12周后，与对照组相比，CB 2 −/−Ldlr−/−病变显示出更高的巨噬细胞含量（86.6 ± 4.1 vs 75.2 ± 7.5%，P < 0.05）和SMC含量（11.1 ± 5.1 vs 4.2 ± 2.4%，P < 0.05）。通过原位TUNEL分析确定，12周后CB 2 −/−Ldlr−/−病变的细胞凋亡减少了约50%。CB 2 −/−Ldlr−/−病变在12周后显示胶原蛋白含量显著降低，弹性蛋白纤维断裂增加，这与基质金属蛋白酶9（MMP）水平增加约57%相关。在体外，CB 2 −/−巨噬细胞分泌的MMP 9活性是CB 2 +/+巨噬细胞的1.8倍。CB 2受体缺陷通过增加病变巨噬细胞和SMC含量、减少病变细胞凋亡和改变细胞外基质成分（部分通过上调MMP 9）影响Ldlr缺失小鼠的动脉粥样硬化形成。这些结果表明，CB 2受体的药理学操作可能对动脉粥样硬化形成和斑块稳定性产生多重和复杂的影响。
To determine if cannabinoid receptor 2 (CB2) plays a role in atherosclerosis, we investigated the effects of systemic CB2 gene deletion on hyperlipidemia-induced atherogenesis in low density lipoprotein receptor-deficient (Ldlr−/−) mice. Ldlr−/− and CB2/Ldlr double knockout (CB2−/−Ldlr−/−) mice were fed an atherogenic diet for 8 and 12 weeks. Morphometric analysis revealed no significant difference between the atherosclerotic lesion area in the proximal aortas of Ldlr−/− and CB2−/−Ldlr−/− mice after 8 or 12 weeks on the atherogenic diet. The macrophage and smooth muscle cell (SMC) content, as revealed by immunohistochemical staining, did not differ significantly between Ldlr−/− and CB2−/−Ldlr−/− lesions after 8 weeks. However, after 12 weeks, CB2−/−Ldlr−/− lesions displayed greater macrophage content (86.6 ± 4.1 versus 75.2 ± 7.5%, P < 0.05) and SMC content (11.1 ± 5.1 versus 4.2 ± 2.4%, P < 0.05) compared to controls. Lesional apoptosis, as determined by in situ TUNEL analysis, was reduced ∼50% in CB2−/−Ldlr−/− lesions after 12 weeks. CB2−/−Ldlr−/− lesions displayed significantly reduced collagen content and increased elastin fiber fragmentation after 12 weeks, which was associated with an ∼57% increase in matrix metalloproteinase 9 (MMP) levels. In vitro, CB2−/− macrophages secreted ∼1.8-fold more MMP9 activity than CB2+/+ macrophages. CB2 receptor deficiency affects atherogenesis in Ldlr-null mice by increasing lesional macrophage and SMC content, reducing lesional apoptosis and altering extracellular matrix components, in part, by upregulating MMP9. These results suggest that pharmacological manipulation of CB2 receptors might exert multiple and complex effects on atherogenesis and plaque stability.
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影响因子：
6.5
作者：
Freeman-Anderson, Natalie E.;Pickle, Theresa G.;Thewke, Douglas P.
通讯作者：
Thewke, Douglas P.
人体免疫组织和白细胞亚群中枢和外周大麻素受体的表达
DOI：
10.1111/j.1432-1033.1995.tb20780.x
发表时间：
1995-08-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
GALIEGUE, S;MARY, S;CASELLAS, P
通讯作者：
CASELLAS, P
影响因子：
3.5
作者：
Kuwae, T;Shiota, Y;Schmid, HHO
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Schmid, HHO
影响因子：
9.3
作者：
Newby, Andrew C.
通讯作者：
Newby, Andrew C.
影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M