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.

METHODS AND 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: Takashi Kohno, Toshihisa Anzai, Hidehiro Kaneko, Yasuo Sugano, Hideyuki Shimizu, Masayuki Shimoda, Taku Miyasho, Minoru Okamoto, Hiroshi Yokota, Shingo Yamada, Tsutomu Yoshikawa, Yasunori Okada, Ryohei Yozu, Satoshi Ogawa, Keiichi Fukuda
• Journal: Journal of cardiology (J Cardiol) Vol. 59 Issue 3 Pg. 299-306 (May 2012) ISSN: 1876-4738 [Electronic] Netherlands
• PMID: 22365948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Chemical References

• HMGB1 Protein
• Inflammation Mediators
• Matrix Metalloproteinases
• Calcium Chloride

Topics

• Animals
• Aorta, Abdominal (metabolism)
• Aortic Aneurysm, Abdominal (etiology, genetics, prevention & control, therapy)
• Calcium Chloride
• Disease Models, Animal
• Gene Expression
• HMGB1 Protein (antagonists & inhibitors, metabolism, physiology)
• Humans
• Inflammation Mediators
• Matrix Metalloproteinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Molecular Targeted Therapy