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.

[1]  S. Takasawa,et al.  Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. , 2003, The Biochemical journal.

[2]  Katharina Hanna,et al.  MCP-1 induces activation of MAP-kinases ERK, JNK and p38 MAPK in human endothelial cells , 2002 .

[3]  J. Heinecke,et al.  Production of N(epsilon)-(carboxymethyl)lysine is impaired in mice deficient in NADPH oxidase: a role for phagocyte-derived oxidants in the formation of advanced glycation end products during inflammation. , 2003, Diabetes.

[4]  J. Sasaki,et al.  In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques. , 2000, Atherosclerosis.

[5]  N. Maeda,et al.  Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Andrassy,et al.  Central role of RAGE-dependent neointimal expansion in arterial restenosis. , 2003, The Journal of clinical investigation.

[7]  Peter Libby,et al.  The immune response in atherosclerosis: a double-edged sword , 2006, Nature Reviews Immunology.

[8]  D. Harats,et al.  Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothelin-1 promoter. , 1995, The Journal of clinical investigation.

[9]  N. Kalinina,et al.  Increased Expression of the DNA-Binding Cytokine HMGB1 in Human Atherosclerotic Lesions: Role of Activated Macrophages and Cytokines , 2004 .

[10]  T. Kislinger,et al.  Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases , 2000, Nature.

[11]  K. O. Elliston,et al.  Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. , 1992, The Journal of biological chemistry.

[12]  Roger G. Chui,et al.  c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells. , 2005, Blood.

[13]  M. Bureau,et al.  Protective role of interleukin-10 in atherosclerosis. , 1999, Circulation research.

[14]  D. Harrison,et al.  Endothelial Regulation of Vasomotion in ApoE-Deficient Mice: Implications for Interactions Between Peroxynitrite and Tetrahydrobiopterin , 2001, Circulation.

[15]  S. Shyue,et al.  Superoxide Dismutase Inhibits the Expression of Vascular Cell Adhesion Molecule-1 and Intracellular Cell Adhesion Molecule-1 Induced by Tumor Necrosis Factor-&agr; in Human Endothelial Cells Through the JNK/p38 Pathways , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[16]  P. Libby,et al.  Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. , 1997, Circulation.

[17]  Leslie A. Smith,et al.  Mechanism of Endothelial Dysfunction in Apolipoprotein E-Deficient Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[18]  V. Maréchal,et al.  HMGB1: un lien entre inflammation septique et non septique , 2009, Revue Francophone des Laboratoires.

[19]  T. Kislinger,et al.  RAGE Blockade Stabilizes Established Atherosclerosis in Diabetic Apolipoprotein E–Null Mice , 2002, Circulation.

[20]  A. Schmidt,et al.  Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts , 1998, Nature Medicine.

[21]  P. Libby,et al.  Reduction of atherosclerosis in mice by inhibition of CD40 signalling , 1998, Nature.

[22]  X. Chen,et al.  Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system , 2003, Nature Medicine.

[23]  Ju Yong Lee,et al.  Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro , 2001, Experimental & Molecular Medicine.

[24]  R. Silverman,et al.  An Apoptotic Signaling Pathway in the Interferon Antiviral Response Mediated by RNase L and c-Jun NH2-terminal Kinase* , 2004, Journal of Biological Chemistry.

[25]  A. Schmidt,et al.  RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes. , 2006, Atherosclerosis.

[26]  A. Schmidt.  Suppression of accelerated diabetic atherosclerosis by soluble receptor for age (srage) , 1998 .

[27]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[28]  M. Runge,et al.  MnSOD Deficiency Increases Endothelial Dysfunction in ApoE-Deficient Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[29]  T. Watanabe,et al.  Nitric oxide inhibits the formation of advanced glycation end products. , 2000, Kidney international.

[30]  T. Kislinger,et al.  RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-α and NF-κB , 2005, The Journal of experimental medicine.

[31]  P. Libby,et al.  Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. , 1998, Molecular cell.

[32]  C. Hedrick,et al.  Glucose Regulates Monocyte Adhesion Through Endothelial Production of Interleukin-8 , 2003, Circulation research.

[33]  M. Neurath,et al.  RAGE Mediates a Novel Proinflammatory Axis A Central Cell Surface Receptor for S100/Calgranulin Polypeptides , 1999, Cell.

[34]  Y. Bobryshev,et al.  S-100 positive cells in human arterial intima and in atherosclerotic lesions. , 1995, Cardiovascular Research.

[35]  E. Abraham,et al.  Involvement of Toll-like Receptors 2 and 4 in Cellular Activation by High Mobility Group Box 1 Protein* , 2004, Journal of Biological Chemistry.

[36]  W. Trojaborg,et al.  RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  R. Ross,et al.  Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[38]  I. Charo,et al.  Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis , 1998, Nature.

[39]  T. Kislinger,et al.  N ε-(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression* , 1999, The Journal of Biological Chemistry.

[40]  K. Tracey,et al.  HMG-1 as a late mediator of endotoxin lethality in mice. , 1999, Science.

[41]  S. Horiuchi,et al.  CD36, serves as a receptor for advanced glycation endproducts (AGE). , 2002, Journal of diabetes and its complications.

[42]  H. Freeze,et al.  N‐Glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth , 2002, Journal of neurochemistry.

[43]  P. Vanhoutte,et al.  Persistence of the Nitric Oxide Pathway in the Aorta of Hypercholesterolemic Apolipoprotein-E-Deficient Mice , 2003, Journal of Vascular Research.

[44]  A. Lusis,et al.  Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins , 1990, Nature.

[45]  Y. Fujita,et al.  Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. , 2004, Experimental cell research.

[46]  J. Luban,et al.  Blockade of Late Stages of Autoimmune Diabetes by Inhibition of the Receptor for Advanced Glycation End Products1 , 2004, The Journal of Immunology.

[47]  Peter P. Nawroth,et al.  Release of High Mobility Group Box 1 by Dendritic Cells Controls T Cell Activation via the Receptor for Advanced Glycation End Products1 , 2005, The Journal of Immunology.

[48]  M. Hartmann,et al.  Myeloid-related Protein (MRP) 8 and MRP14, Calcium-binding Proteins of the S100 Family, Are Secreted by Activated Monocytes via a Novel, Tubulin-dependent Pathway* , 1997, The Journal of Biological Chemistry.

[49]  M. Cybulsky,et al.  Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. , 1991, Science.

[50]  J. Soria,et al.  Inhibition of endothelial cell migration by cerivastatin, an HMG‐CoA reductase inhibitor: contribution to its anti‐angiogenic effect , 2001, FEBS letters.