Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression.
Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression.
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DOI：
10.1161/atvbaha.112.300329
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Dalman RL
中科院分区：
文献类型：
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作者：
Iida Y;Xu B;Xuan H;Glover KJ;Tanaka H;Hu X;Fujimura N;Wang W;Schultz JR;Turner CR;Dalman RL
大动脉瘤是腹主动脉瘤（AAA）疾病的关键因素。我们检测了MKEY（一种CXCL 4-CCL 5相互作用的肽抑制剂）影响小鼠模型中AAA进展的能力。在10周龄雄性C57 BL/6小鼠中通过短暂肾下主动脉猪胰弹性蛋白酶（PPE）输注产生AAA。1）PPE输注前，或2）动脉瘤开始后，通过静脉内注射MKEY治疗小鼠。免疫组化显示，CCL 5和CCR 5分别在囊泡和壁单核细胞/巨噬细胞上表达。MKEY治疗部分抑制受体小鼠中适应性转移白细胞的透壁AAA迁移。虽然所有溶剂预处理的小鼠均发生AAA，但在10和20 mg /kg MKEY预处理的小鼠中，分别仅60%（3/5）和14%（1/7）形成动脉瘤。MKEY预处理减少PPE输注后主动脉直径增大，保留中膜弹性蛋白纤维和平滑肌细胞，并减弱壁巨噬细胞浸润、血管生成和主动脉MMP 2和9表达。PPE输注后开始的MKEY也稳定和/或减少了现有AAA的扩大。最后，MKEY治疗有效限制血管紧张素II输注后载脂蛋白E缺陷小鼠AAA的形成。MKEY在两个互补的实验模型中抑制AAA的形成和进展。CXCL 4-CCL 5相互作用的肽抑制可能代表了限制人类AAA疾病进展的可行翻译策略。
Macrophages are critical contributors in abdominal aortic aneurysm (AAA) disease. We examined the ability of MKEY, a peptide inhibitor of CXCL4-CCL5 interaction, to influence AAA progression in murine models. AAAs were created in 10-week-old male C57BL/6 mice by transient infrarenal aortic porcine pancreatic elastase (PPE) infusion. Mice were treated with MKEY via intravenous injection either 1) before PPE infusion, or 2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited transmural AAA migration of adaptively transferred leukocytes in recipient mice. While all vehicle-pretreated mice developed AAA, aneurysms formed in only 60% (3/5) and 14% (1/7) of mice pretreated with MKEY at 10 and 20 mg /kg, respectively. MKEY pretreatment reduced aortic diameter enlargement, preserved medial elastin fibers and smooth muscle cells, and attenuated mural macrophage infiltration, angiogenesis, and aortic MMP2 & 9 expression following PPE infusion. MKEY initiated after PPE infusion also stabilized and/or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation following angiotensin II infusion in apolipoprotein E deficient mice. MKEY suppresses AAA formation and progression in two complementary experimental models. Peptide inhibition of CXCL4-CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.