Alamandine abrogates neutrophil degranulation in atherosclerotic mice
Alamandine abrogates neutrophil degranulation in atherosclerotic mice
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DOI：
10.1111/eci.12708
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发表时间：
2017-02-01
影响因子：
5.5
通讯作者：
Montecucco, Fabrizio
中科院分区：
文献类型：
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作者：
Da Silva, Analina R.;Lenglet, Sebastien;Montecucco, Fabrizio
背景 最近发现中性粒细胞介导的炎症是动脉粥样硬化进展的一个积极因素。假设抑制中性粒细胞脱粒或募集的治疗策略对斑块易损性产生积极影响。在本研究中，我们研究了最近发现的 Mas 相关 G 偶联受体 D 型 (MrgD) 阿拉曼定激动剂的治疗是否会影响体内和体外中性粒细胞脱粒。 材料和方法 15 周龄的 ApoE(-/-) 小鼠用西式饮食喂养另外 11 周。经过前两周的饮食后，小鼠通过手术植入了颈动脉“铸型”装置，该装置可以改变血液剪切应力并诱导不同的颈动脉斑块表型。在安乐死前的最后 4 周内，小鼠被随机分配至通过微泵皮下注射媒介物 (NaCl 0.15 M) 或阿拉曼定 (24 lg/kg/h)。体外实验中，ApoE(-/-)小鼠腹腔注射硫代乙醇酸后获得中性粒细胞。结果阿拉曼丁治疗耐受性良好，但未能影响颈动脉和主动脉根部斑块内的脂质、巨噬细胞、中性粒细胞或胶原含量。此外，金刚烷胺治疗并不影响淋巴器官中 Th 细胞的极化。相反，服用金刚烷胺与中性粒细胞颗粒酶（例如 MMP-9 和 MPO）以及主动脉根斑块内 MMP-9 含量的血清水平降低相关。在体外，与阿拉曼定预孵育剂量依赖性地消除了 PMA 诱导的中性粒细胞 MMP-9 和 MPO 脱颗粒。结论这些结果表明，用 MrgD 激动剂阿拉曼定治疗导致中性粒细胞颗粒产物释放减少，可能干扰促动脉粥样硬化中性粒细胞激活。
Background Neutrophil-mediated inflammation was recently identified as an active contributor to athero-progression. Therapeutic strategies inhibiting neutrophil degranulation or recruitment were hypothesized to positively impact on plaque vulnerability. In this study, we investigated whether treatment with the recently discovered agonist of the Mas-related G-coupled receptor type D (MrgD) alamandine would impact on neutrophil degranulation in vivo and in vitro.Materials and methods Fifteen-week-old ApoE(-/-) mice were fed with a Western-type diet for an additional 11 weeks. After the first 2 weeks of diet, mice were surgically implanted with a carotid 'cast' device that alters the blood shear stress and induces different carotid plaque phenotypes. During the last 4 weeks before euthanasia, mice were randomly assigned to subcutaneously receive vehicle (NaCl 0.15 M) or alamandine (24 lg/kg/h) by micropump. For in vitro experiments, neutrophils were obtained after thioglycollate intraperitoneal injection in ApoE(-/-) mice.Results Treatment with alamandine was well-tolerated, but failed to affect lipid, macrophage, neutrophil or collagen content within carotid and aortic root plaques. Also, treatment with alamandine did not affect Th-cell polarization in lymphoid organs. Conversely, alamandine administration was associated with a reduction in serum levels of neutrophil granule enzymes, such as MMP-9 and MPO as well as MMP-9 content within aortic root plaques. In vitro, preincubation with alamandine dose-dependently abrogated PMA-induced neutrophil degranulation of MMP-9 and MPO.Conclusion These results suggest that treatment with the MrgD agonist alamandine led to a reduced release of neutrophil granule products, potentially interfering with pro-atherosclerotic neutrophil activation.