Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice.
Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE-/- mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.
Harja
Evis
E
Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA.
Bu
De-xiu
DX
Hudson
Barry I
BI
Chang
Jong Sun
JS
Shen
Xiaoping
X
Hallam
Kellie
K
Kalea
Anastasia Z
AZ
Lu
Yan
Y
Rosario
Rosa H
RH
Oruganti
Sai
S
Nikolla
Zana
Z
Belov
Dmitri
D
Lalla
Evanthia
E
Ramasamy
Ravichandran
R
Yan
Shi Fang
SF
Schmidt
Ann Marie
AM
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D039841:Leukocyte L1 Antigen Complex / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*
D001057:Apolipoproteins E; D000939:Epitopes; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D039841:Leukocyte L1 Antigen Complex; D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic