Anti-receptor for advanced glycation end products therapies as novel treatment for abdominal aortic aneurysm.
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.
Zhang
Fan
F
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Kent
K Craig
KC
Yamanouchi
Dai
D
Zhang
Yan
Y
Kato
Kaori
K
Tsai
Shirling
S
Nowygrod
Roman
R
Schmidt
Ann Marie
AM
Liu
Bo
B
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D020780:Matrix Metalloproteinase 9