Anti-RAGE Therapies as Novel Treatment for Abdominal Aortic Aneurysm
*Fan Zhang1, *Bo Liu1, *Dai Yamanouchi1, *Yan Zhang2, *Kaori Kato1, *Shirling Tsai3, *Roman Nowygrod2, *Ann Marie Schmidt2, Craig K Kent1
1University of Wisconsin School of Medison, Madison, WI;2Columbia University Medical Center, New York, NY;3Weill Medical School, Cornell University, New York, NY
Objective: Rupture of abdominal aortic aneurysms (AAA) is a devastating event preventable by therapies that inhibit growth of small aneurysms. RAGE (Receptor of advanced glycation end products) has been implicated in age related diseases including vascular restenosis and Alzheimer’s. Consequently, we explored whether RAGE may also contribute to the formation of AAAs.
Results: Implicating a role for RAGE in AAA, we found RAGE to be highly expressed in human aneurysm specimens and absent in normal aortic tissue. In a mouse model of AAA, RAGE gene deletion (knockout) dramatically reduced the incidence of AAA to 1/3 that of control (AAAs in 25.0% of knockouts versus 75.0% controls). Moreover, aortic diameter was markedly reduced in RAGE knockout animals versus controls (1.3 + 0.48 versus 2.1 + 0.57mm). As to mechanism, we found that RAGE was co-expressed in AAA macrophages with MMP-9, a promoter of matrix degradation known to induce AAA. In vitro, RAGE induced the production of MMP-9 in macrophages in a dose-dependent manner while blocking RAGE signaling with a soluble RAGE inhibitor prevented MMP-9 expression.
Conclusions: RAGE promotes the development of AAA by inducing MMP-9 expression. Blocking RAGE in mice has a dramatic effect on the formation of AAA. 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.