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Anti-Receptor for Advanced Glycation End Products Therapies as Novel Treatment for Abdominal Aortic Aneurysm

Zhang, Fan MD, PhD*; Kent, K Craig MD*; Yamanouchi, Dai MD, PhD*; Zhang, Yan†; Kato, Kaori MD*; Tsai, Shirling MD‡; Nowygrod, Roman MD†; Schmidt, Ann Marie MD†; Liu, Bo MD, PhD*‡

Annals of Surgery:
doi: 10.1097/SLA.0b013e3181b41a18
Original Articles
Abstract

Objective: Rupture of abdominal aortic aneurysms (AAA) is a devastating event potentially preventable by therapies that inhibit growth of small aneurysms. Receptor of advanced glycation end products (RAGE) has been implicated in age related diseases including atherosclerosis and Alzheimer. Consequently, we explored whether RAGE may also contribute to the formation of AAAs.

Results: Implicating a role for RAGE in AAA, we found the expression of RAGE and its ligand AGE were highly elevated in human aneurysm specimens as compared with normal aortic tissue. In a mouse model of AAA, RAGE gene deletion (knockout) dramatically reduced the incidence of AAA to 1/3 of control (AAAs in 75.0% of controls vs. 25.0% knockouts). Moreover, aortic diameter was markedly reduced in RAGE knockout animals versus controls. As to mechanism, we found that RAGE was coexpressed in AAA macrophages with MMP-9, a promoter of matrix degradation, which is known to induce AAA. In vitro, AGE induced the production of MMP-9 in macrophages in a dose-dependent manner while blocking RAGE signaling with a soluble AGE inhibitor prevented MMP-9 expression. In vivo, RAGE gene deficiency eliminated MMP-9 activity that was prevalent in aneurismal wall of the wild-type mice.

Conclusions: RAGE promotes the development of AAA by inducing MMP-9 expression. Blocking RAGE in a mouse aneurysm model has a dramatic inhibitory effect on the formation of aneurysms. These data suggest that larger animal and eventually human trials should be designed to test oral RAGE inhibitors and their potential to prevent progression of small aneurysms.

In Brief

This study shows that the receptor of advanced glycation end products (RAGE) and its ligand advanced glycation end products (AGE) were highly elevated in human aneurysm specimens. In a mouse model of abdominal aortic aneurysms (AAA), RAGE gene knockout dramatically reduced the incidence of AAA. RAGE was coexpressed in AAA macrophages with MMP-9. AGE induced the production of MMP-9 in macrophages. These results suggest that RAGE promotes the development of AAA by inducing MMP-9 expression.

Author Information

From the *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI; †Columbia University, College of Physicians and Surgeons, Department of Surgery, New York, NY; and ‡Department of Surgery, Weill Medical College of Cornell University, New York, NY.

Supported by Public Health Service Grants (R01 HL-68673) and R01-HL 081424 (to K.C.K. and B.L.) from National Heart, Lung, and Blood Institute, and Start-up grant from Columbia University Department of Surgery (to F.Z.) and National Institutes of Health Training grants (F32 HL088818-01) (to S.T.).

Reprints: K. Craig Kent, MD, 600 Highland Avenue, CSC/H4-710, Madison, WI 53792. E-mail: kent@surgery.wisc.edu.

© 2009 Lippincott Williams & Wilkins, Inc.