Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Aortic Aneurysm Initiation and Progression in Mice
Objective—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.
Methods and Results—AAAs were created in 10-week-old male C57BL/6 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 transmural AAA migration of adaptively transferred leukocytes in recipient mice. Although 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 metalloproteinase 2 and 9 expression after porcine pancreatic elastase infusion. MKEY initiated after porcine pancreatic elastase infusion also stabilized and reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation after angiotensin II infusion in apolipoprotein E–deficient mice.
Conclusion—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.
- Received August 21, 2012.
- Accepted December 12, 2012.
- © 2013 American Heart Association, Inc.