title: High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm.
abstract: BACKGROUND
  Abdominal aortic aneurysm (AAA) expansion is characterized by chronic inflammatory cell infiltration and extracellular matrix degradation. High-mobility group box 1 protein (HMGB1) is one of the damage-associated molecular pattern molecules derived from injured/necrotic and activated inflammatory cells. We investigated the expression of HMGB1 in human AAA and mouse experimental AAA. Then, we evaluated the effect of HMGB1 blockade on AAA formation in the mouse model.
  
  
  RESULTS
  Human AAA samples showed increased HMGB1 expression compared with normal aortic wall. In a mouse CaCl(2)-induced AAA model, the expression of HMGB1 was increased compared with that in sham, and was positively correlated with matrix metalloproteinase (MMP)-2 and MMP-9 activity. We administered neutralizing anti-HMGB1 antibody (AAA/anti-H) or control antibody (AAA/C) to AAA mice subcutaneously every 3 days for 6 weeks. Treatment with neutralizing anti-HMGB1 antibody suppressed AAA formation, and attenuated elastin fragmentation. HMGB1 blockade markedly reduced the number of macrophages and MMP-2 and MMP-9 activity in aneurysmal tissue. The mRNA level of tumor necrosis factor-α and CD68 in the aorta was reduced in AAA/anti-H compared with AAA/C.
  
  
  CONCLUSIONS
  Elevation of HMGB1 level in aneurysmal tissue was observed in human AAA and mouse experimental AAA. HMGB1 blockade in a mouse AAA model reduced AAA progression, in association with reduced infiltration of macrophages and MMPs activity. These findings suggest a significant role for HMGB1 in the pathogenesis of AAA.
authors.affiliation: Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kaneko
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugano
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.forename: Taku
authors.initials: T
authors.lastname: Miyasho
authors.forename: Minoru
authors.initials: M
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokota
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yozu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control* / Q000628:therapy; D002122:Calcium Chloride; D004195:Disease Models, Animal; D015870:Gene Expression; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy
chemical_list: D024243:HMGB1 Protein; D018836:Inflammation Mediators; D020782:Matrix Metalloproteinases; D002122:Calcium Chloride