Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA 94305-5102, USA.
Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):718-26. doi: 10.1161/ATVBAHA.112.300329. Epub 2013 Jan 3.
Macrophages are critical contributors to 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/6J mice by transient infrarenal aortic porcine pancreatic elastase infusion. Mice were treated with MKEY via intravenous injection either (1) before porcine pancreatic elastase infusion or (2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited migration of adaptively transferred leukocytes into aneurysmal aortae in recipient mice. Although all vehicle-pretreated mice developed AAAs, 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 metalloproteinase 2 and 9 expression after porcine pancreatic elastase infusion. MKEY initiated after porcine pancreatic elastase infusion also stabilized or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation after angiotensin II infusion in apolipoprotein E-deficient mice.
MKEY suppresses AAA formation and progression in 2 complementary experimental models. Peptide inhibition of CXCL4-CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.
巨噬细胞是腹主动脉瘤（AAA）疾病的关键贡献者。我们研究了 MKEY（一种 CXCL4-CCL5 相互作用的肽抑制剂）在小鼠模型中影响 AAA 进展的能力。
通过短暂的肾下主动脉猪弹性蛋白酶输注在 10 周龄雄性 C57BL/6J 小鼠中创建 AAA。通过静脉注射用 MKEY 治疗小鼠，要么（1）在猪弹性蛋白酶输注之前，要么（2）在动脉瘤起始后。免疫染色显示 CCL5 和 CCR5 分别在动脉瘤主动脉和壁单核细胞/巨噬细胞上表达。MKEY 治疗部分抑制了适应性转移白细胞进入接受小鼠的动脉瘤主动脉的迁移。尽管所有用载体预处理的小鼠均形成 AAA，但在用 10 和 20 mg/kg 的 MKEY 预处理的小鼠中，分别仅在 60%（3/5）和 14%（1/7）的小鼠中形成 AAA。MKEY 预处理可减少主动脉直径增大，保持中膜弹性纤维和平滑肌细胞，并减轻壁巨噬细胞浸润、血管生成以及猪弹性蛋白酶输注后主动脉基质金属蛋白酶 2 和 9 的表达。猪弹性蛋白酶输注后开始的 MKEY 也稳定或减少了现有 AAA 的增大。最后，MKEY 治疗在载脂蛋白 E 缺乏小鼠的血管紧张素 II 输注后有效限制了 AAA 的形成。
MKEY 在 2 种互补的实验模型中抑制 AAA 的形成和进展。CXCL4-CCL5 相互作用的肽抑制可能代表一种可行的转化策略，可限制人类 AAA 疾病的进展。
