title: Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA 94305-5102, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Iida
authors.forename: Baohui
authors.initials: B
authors.lastname: Xu
authors.forename: Haojun
authors.initials: H
authors.lastname: Xuan
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Glover
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Hu
authors.forename: Naoki
authors.initials: N
authors.lastname: Fujimura
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Schultz
authors.forename: Court R
authors.initials: CR
authors.lastname: Turner
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Dalman
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D007275:Injections, Intravenous; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010196:Pancreatic Elastase; D010978:Platelet Factor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D009842:Oligopeptides; D019713:Receptors, CCR5; D000804:Angiotensin II; D010978:Platelet Factor 4; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse