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

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's. 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 to 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 versus 25.0% knockouts). Moreover, aortic diameter was markedly reduced in RAGE knockout animals versus controls. As to mechanism, we found that RAGE was co-expressed in AAA macrophages with MMP-9, a promoter of matrix degradation, which is known to induce AAA. In vitro, advanced glycation end products (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.

Recombinant Human Thrombomodulin Suppresses Experimental Abdominal Aortic Aneurysms Induced by Calcium Chloride in Mice

“…1D). Consistent with previous observations from the angiotensin II-infusion model, 35 RAGE was observed mainly in MOMA-1-positive macrophages and, to a lesser extent, in α-SMA-positive SMCs (Fig. 1E).…”

“…15,16,31,33 Recently, RAGE has also been implicated in AAA. 35 In the CaCl 2 -induced model, RAGE was remarkably increased on day 3 compared with that in NaCl-group mice and persisted at a high level during the 28-day period of AAA formation (Fig. 1C).…”

Role of High Mobility Group Box 1 (HMGB1) in Wound Healing

“…Activation of RAGE induces a down-regulation of genes involved in collagen synthesis and an up-regulation of matrix metalloproteinase-8 (MMP-8) and MMP-9 genes [20]. Furthermore, RAGE knockout mice demonstrate reduced MMP-9 activity [21].…”

Panax Notogingseng Saponins Suppress RAGE/ MAPK Signaling and NF-kappaB Activation in Apolipoprotein-E-deficient Atherosclerosis-prone mice

“…It has been found that PNS have an anti-inflammatory activity beyond its antioxidant property [14,15,19,20]. The pro-inflammatory factors including VCAM-1, ICAM-1 and MCP-1 are responsible for the accumulation of macrophages into the atheroma-prone area.…”