Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice.
Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice.
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DOI：
10.1126/scitranslmed.aaa1065
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发表时间：
2015-02-18
影响因子：
17.1
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Fredman G;Kamaly N;Spolitu S;Milton J;Ghorpade D;Chiasson R;Kuriakose G;Perretti M;Farokzhad O;Tabas I
慢性、非消退性炎症是晚期动脉粥样硬化病变临床进展的关键因素。在正常的炎症反应中，消退是由几种激动剂介导的，其中包括糖皮质激素调节的蛋白质，称为膜联蛋白A1。膜联蛋白A1的促分解作用是通过其受体N-甲酰肽受体2（FPR 2/ALX）介导的，可以通过包含氨基酸2-26（Ac 2 -26）的氨基末端肽来模拟。在脂肪喂养的Ldlr−/−小鼠中，评价了含有Ac 2 -26的IV型胶原蛋白（Col IV）靶向纳米颗粒（NP）对慢性晚期动脉粥样硬化的治疗作用。当给予具有预先存在的病变的小鼠时，Col IV-Ac 2 -26 NP靶向病变并导致关键晚期斑块性质的显著改善，包括覆盖病变的保护性胶原蛋白层的增加（其与病变胶原酶活性的降低相关）、氧化应激的抑制和斑块坏死的减少。在骨髓细胞中缺乏FPR 2/ALX的小鼠中，没有看到这些改善。因此，在靶向NP中施用消退介导肽激活其在骨髓细胞上的受体以稳定晚期动脉粥样硬化病变。这些发现支持了炎症消退缺陷在晚期动脉粥样硬化中起作用的概念，并提出了一种新的治疗形式。
Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26 (Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.
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影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
影响因子：
20.1
作者：
Libby P;Tabas I;Fredman G;Fisher EA
通讯作者：
Fisher EA
DOI：
10.1016/j.carpath.2012.06.006
发表时间：
2013-01
期刊：
Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology
影响因子：
--
作者：
Gimbrone MA Jr;García-Cardeña G
通讯作者：
García-Cardeña G
DOI：
10.1161/atvbaha.112.249508
发表时间：
2012-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Norling LV;Dalli J;Flower RJ;Serhan CN;Perretti M
通讯作者：
Perretti M
影响因子：
30.5
作者：
Haworth, Oliver;Cernadas, Manuela;Levy, Bruce D.
通讯作者：
Levy, Bruce D.