The effect of soluble RAGE on inhibition of angiotensin II-mediated atherosclerosis in apolipoprotein E deficient mice.
BACKGROUND
The cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO).


RESULTS
9 week old Apo E KO mice were infused subcutaneously with AngII (1 µg/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 µg, 1 µg, to 2 µg/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 µg, 1 µg, and 2 µg of sRAGE in AngII group resulted in the dose-dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells.


CONCLUSIONS
The results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII-induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation.
Graduate Program in Science for Aging and Yonsei Research Institute of Aging Science, Yonsei University, Seoul, Republic of Korea.
Dajeong
D
Lee
Kyung Hye
KH
Lee
Hyelim
H
Park
Soo Hyuk
SH
Kim
Taewon
T
Jin
Soyoung
S
Cho
Ji Hyung
JH
Chung
Soyeon
S
Lim
Sungha
S
Park
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility
D001057:Apolipoproteins E; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000804:Angiotensin II