人类SELP转基因表达的P-选择素在载脂蛋白E缺陷小鼠中具有致动脉粥样硬化作用。
P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E-Deficient Mice.
作者信息
Zhang Nan, Liu Zhenghui, Yao Longbiao, Mehta-D'souza Padmaja, McEver Rodger P
机构信息
From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (N.Z., R.P.M.); and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (Z.L., L.Y., P.M.-D., R.P.M.).
出版信息
Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1114-21. doi: 10.1161/ATVBAHA.116.307437. Epub 2016 Apr 21.
OBJECTIVE
During inflammation, P-selectin expressed on activated endothelial cells and platelets mediates rolling adhesion of leukocytes. Atherosclerosis-prone mice crossed with P-selectin-deficient (Selp(-/-)) mice develop smaller lesions. Cytokines, such as tumor necrosis factor-α, increase Selp transcripts and augment atherosclerosis in mice. However, they decrease SELP transcripts in humans, challenging assumptions that human P-selectin is atherogenic. We used mice expressing a human SELP transgene to examine the atherogenic role of P-selectin.
APPROACH AND RESULTS
We crossed apolipoprotein E-deficient (Apoe(-/-)) mice with Selp(-/-) mice or transgenic mice expressing the entire human SELP gene (TgSELP(+/-)). Aortas developed larger, macrophage-rich atheromas in Apoe(-/-)Selp(-/-)TgSELP(+/-) mice than in Apoe(-/-)Selp(-/-) mice after 8 or 16 weeks on a Western diet. Confocal microscopy of Apoe(-/-)Selp(-/-)TgSELP(+/-) aortas revealed staining for human P-selectin in endothelial cells overlying atheromas but not in lesional macrophages. We also observed staining for human P-selectin in aortic endothelial cells of 3- to 4-week-old Apoe(-/-)Selp(-/-)TgSELP(+/-) weanlings before atheromas developed. Furthermore, human SELP transcripts were ≈3-fold higher in aortas of Apoe(-/-)Selp(+/-)TgSELP(+/-) weanlings than in Selp(+/-)TgSELP(+/-) weanlings, whereas murine Selp and Sele transcripts were equivalent in weanlings of both genotypes. Human SELP transcripts in aortas of Apoe(-/-)Selp(+/-)TgSELP(+/-) mice remained nearly constant during 16 weeks on a Western diet, whereas murine Selp and Sele transcripts progressively increased. Bone marrow transplantation in Apoe(-/-)Selp(-/-) and Apoe(-/-)Selp(-/-)TgSELP(+/-) mice demonstrated that both platelets and endothelial cells must express human P-selectin to promote atherogenesis.
CONCLUSIONS
P-selectin expressed by human SELP is atherogenic in Apoe(-/-) mice, suggesting that P-selectin contributes to atherogenesis in humans.
目的
在炎症过程中，活化内皮细胞和血小板上表达的P选择素介导白细胞的滚动黏附。易患动脉粥样硬化的小鼠与P选择素缺陷（Selp(-/-)）小鼠杂交后病变较小。细胞因子，如肿瘤坏死因子-α，可增加Selp转录本并加重小鼠动脉粥样硬化。然而，它们会降低人类的SELP转录本，这对人类P选择素具有致动脉粥样硬化作用的假设提出了挑战。我们使用表达人类SELP转基因的小鼠来研究P选择素的致动脉粥样硬化作用。
方法与结果
我们将载脂蛋白E缺陷（Apoe(-/-)）小鼠与Selp(-/-)小鼠或表达整个人类SELP基因的转基因小鼠（TgSELP(+/-)）进行杂交。在西方饮食喂养8周或16周后，Apoe(-/-)Selp(-/-)TgSELP(+/-)小鼠的主动脉中形成了比Apoe(-/-)Selp(-/-)小鼠更大、富含巨噬细胞的动脉粥样硬化斑块。对Apoe(-/-)Selp(-/-)TgSELP(+/-)小鼠主动脉进行共聚焦显微镜检查发现，动脉粥样硬化斑块上方的内皮细胞中有人类P选择素染色，但病变巨噬细胞中没有。我们还在3至4周龄动脉粥样硬化斑块尚未形成的Apoe(-/-)Selp(-/-)TgSELP(+/-)断奶小鼠的主动脉内皮细胞中观察到了人类P选择素染色。此外，Apoe(-/-)Selp(+/-)TgSELP(+/-)断奶小鼠主动脉中的人类SELP转录本比Selp(+/-)TgSELP(+/-)断奶小鼠高约3倍，而两种基因型断奶小鼠中的小鼠Selp和Sele转录本相当。在西方饮食喂养16周期间，Apoe(-/-)Selp(+/-)TgSELP(+/-)小鼠主动脉中的人类SELP转录本几乎保持不变，而小鼠Selp和Sele转录本则逐渐增加。对Apoe(-/-)Selp(-/-)和Apoe(-/-)Selp(-/-)TgSELP(+/-)小鼠进行骨髓移植表明，血小板和内皮细胞都必须表达人类P选择素才能促进动脉粥样硬化的发生。
结论
人类SELP表达的P选择素在Apoe(-/-)小鼠中具有致动脉粥样硬化作用，提示P选择素在人类动脉粥样硬化发生中起作用。
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