© 1999 American Heart Association, Inc.
Mini Review |
Activation of Receptor for Advanced Glycation End Products
A Mechanism for Chronic Vascular Dysfunction in Diabetic Vasculopathy and Atherosclerosis
From the Division of Surgical Science, Departments of Surgery (A.M.S., D.S.), Medicine (A.M.S.), Pathology (S.D.Y.), and Physiology (D.S.) and Cellular Biophysics (A.M.S., S.D.Y, D.S.), College of Physicians & Surgeons of Columbia University, New York, NY, and Laboratoire de Biologie Vasculaire et Cellulaire (J-L.W.), UFR Lariboisiere St Louis, Paris, France.
Correspondence to Dr Ann Marie Schmidt, Department of Surgery, P&S 17-501, College of Physicians & Surgeons of Columbia University, 630 W 168th St, New York, NY 10032.
Abstract
Abstract—Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid ß peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.
Key Words: glycoxidation • diabetes • nuclear factor-
B • inflammation • amyloid
Studies of proinflammatory cytokines have
provided vascular biologists with important insights into the
pathogenesis of the acute inflammatory response, either locally or in
sepsis. Rapid production of mediators such as tumor necrosis
factor-
and other cytokines/chemokines induced leukocyte
adherence to the vessel wall and activation, a diminished vascular
barrier function, an altered vasomotor tone, and a pronounced shift in
hemostatic mechanisms favoring procoagulant events.1 2 3
One of the key facets of this acute host response derives from its
limited duration; levels of cytokines/chemokines quickly decay,
and evidence of cellular activation recedes. Much less is known about
mechanisms underlying the pathogenesis of chronic vascular lesions in
which cellular activation and dysfunction occur over years. The
best-studied example of sustained vascular perturbation results from
elevated levels of plasma lipids/lipoproteins which, by themselves,
induce atherosclerosis in genetically manipulated
mice.4 5 6 7
Diabetes provides a distinct model of chronic vascular disease in which disordered glucose homeostasis triggers abnormalities eventuating in dysfunction of virtually every organ, deriving, in part, from vascular perturbation. Although superimposition of other risk factors, such as hyperlipemia or hypertension, adds to the complex atherogenic milieu, diabetes by itself is a well-recognized independent cardiovascular risk factor.8 9 10 11 12 In fact, up to 80% of deaths in patients with diabetes are closely associated with vascular disease. The impact of diabetic complications in economic terms is emphasized by the consumption by diabetic patients of the largest share of the health care dollar in the United States compared with any other single disease.
Several candidate mechanisms contributing to perturbation of vascular properties in diabetes have been proposed. Two such mechanisms that have received wide attention include the polyol pathway and diacylglycerol-mediated activation of protein kinase C. Elevated flux of metabolites through the polyol pathway results in excess generation of sorbitol, decreased myoinositol uptake, and diminished Na/K ATPase activity and has been suggested as a means of globally perturbing cellular functions in the setting of hyperglycemia.13 However, the most striking benefit of aldose reductase inhibitors studied to date has been in models of neuropathy, and their efficacy in the clinical setting has been less than expected to date. Hyperglycemia-mediated activation of protein kinase C, resulting in recruitment of effector mechanisms causing increased vascular permeability and ameliorating retinopathy, has been demonstrated.10 14 15 The apparent success of selective inhibitor protein kinase CßII in preventing early changes in vascular barrier function and retinopathy16 leaves us now poised to meet the challenge of demonstrating efficacy in models of chronic organ system dysfunction most characteristic of diabetes. The proposed association of sustained activation of protein kinase C with diabetes will require especially careful analysis, as it contrasts with the well-known short-term activation of protein kinase C isoforms well known to be followed by a state refractory to subsequent stimulation. This Mini Review focuses on another mechanism proposed to contribute to diabetic vasculopathy, the accumulation of glycoxidation products that occur in the extracellular space and within cells of the vessel wall10 17 18
Glycoxidation Products: Hyperglycemia, Molecular Turnover, and Oxidant Stress
Although virtually any polypeptide can be subject to glycoxidation posttranslational modification over time, 3 factors have been recognized as critical to the formation of glycoxidation products10 19 20 21 : the extent of hyperglycemia, the turnover of substrates for glycoxidation, and the pro-oxidant nature of the tissue microenvironment. In the setting of hyperglycemia, nonenzymatic glycoxidation results from the interaction of aldoses, such as glucose, with free amino groups on polypeptides or lipids. Formation of early glycation end products, such as Schiff bases and Amadori products, the best-known of which is hemoglobin A1c, is reversible. Further molecular rearrangements, often involving oxidation, eventuate in the formation of advanced glycation end products (AGEs).17 Recent studies from Dr Michael Brownlee's laboratory have emphasized the accelerated time course for intracellular glycoxidation in an environment with elevated levels of glucose, resulting in high concentrations of intracellular aldose phosphates, which enhance glycation compared with aldoses alone. Such intracellular glycoxidation has been shown to alter properties of critical growth factors, such as fibroblast growth factor.18 22 Once formed, AGE-protein adducts, such as carboxymethyl-lysine and pentosidine linked to polypeptides,20 21 23 are quite stable and, in fact, virtually irreversible. Although there are many other AGE-related chemical structures likely to be present in deposits of AGEs found in the vasculature and other tissues (eg, pyrralines that form as a result of glycation alone), carboxymethyl-lysine-protein adducts are the predominant AGEs present in vivo.21 24 25 26 27 For example, carboxymethyl-lysine epitopes are increased at sites of atherosclerotic lesions, especially in patients with concomitant diabetes.10 17 26 27 28 29 30 Pentosidine, a key AGE cross-link, has also been identified at pathological sites, and cross-link–induced increased tissue rigidity could have important functional and architectural effects on mechanical properties of tissues.20 21 31 32 33 34 35 36 Probably the most relevant recent insights in AGE biology concern the association of AGEs with sustained oxidant stress; thus, situations in which the local redox potential has been shifted to favor oxidant stress, as at inflammatory loci or, more generally, in patients with renal failure, AGE formation is substantially enhanced.23 37 38 39 Taken together, these findings indicate that although AGEs may have been previously considered to be restricted to diabetes, it is now recognized that oxidation alone can lead to AGE formation and AGEs have been identified in atherosclerotic tissues without diabetes (see references above). The association of AGEs with factors other than hyperglycemia is underscored by their occurrence in amyloidoses, in which tissue accumulation of amyloidogenic polypeptides occurs. Dialysis-related amyloidosis occurs in patients on long-term hemodialysis and results from the accumulation of amyloid largely composed of ß2-microglobulin in joint tissues.40 Clinically, this disorder is characterized by periarticular soft-tissue swelling, diffuse destructive arthropathy, and subchondral bone erosions and cysts.40 41 Study of ß2-microglobulin from patient-derived tissues has demonstrated the abundance of an AGE-modified form42 43 probably due to the concerted effects of delayed macromolecular turnover and renal failure in driving glycoxidation. In Alzheimer disease, AGE modification of paired helical filament tau31 44 45 and of amyloid ß peptide (Aß)46 has also been observed in patients without diabetes or renal insufficiency, consistent with AGE modification of macromolecules the turnover of which has been delayed by other pathological processes. In each of these situations, glycoxidation superimposed on amyloid deposition is likely to increase the pathogenicity of the amyloid by virtue of the ability of AGEs to form cross-links, to generate reactive oxygen species, and to interact with cellular receptors (see below). Because the formation of AGEs appears to be virtually irreversible, their accumulation in tissues imparts, likely, a chronic, long-term "memory" for previous perturbations and could render the host response to future challenges quite different from that observed in normal tissues.
Cellular Interactions of AGEs: Central Role of Receptor for AGE (RAGE)
Experiments with AGEs prepared in vitro, made by incubating a variety of proteins (especially albumin) with high concentrations of aldoses/aldose phosphates, or more limited studies with AGEs derived from in vivo sources, have demonstrated a spectrum of altered cellular properties. For example, in the endothelium, AGEs diminish vascular barrier function, enhance expression of vascular cell adhesion molecule-1 (VCAM-1), quench nitric oxide, and alter the balance of cellular coagulant properties, in part through induction of procoagulant tissue factor.47 48 49 50 51 These cellular effects of AGEs are largely mediated by their specific engagement of cell surface molecules. Our studies have led to the identification, cloning, and analysis of RAGE, the best-characterized signal transduction receptor for AGEs.37 52 The type A macrophage scavenger receptor53 and other polypeptides potentially present on the cell surface (p60/p90/galectin-2) have also been identified as possible AGE binding sites.50 54 The role of these other AGE binding sites in AGE-mediated cellular activation remains to be determined. However, the scavenger receptor may exert its effect principally at the level of endocytotic clearance of AGEs,55 and it is possible that p60/p90/galectin-2 recognizes different AGE structures compared with RAGE. Because of the incomplete information available on these binding sites in AGE biology, it is premature to make detailed comparisons between these molecules and RAGE, and this issue will not be discussed further in this brief review.
RAGE is a member of the immunoglobulin superfamily of cell surface
molecules, and its extracellular portion, including 332 amino acids,
comprises 1 V-type domain followed by 2 C-type
domains.37 56 57 Structural determinants in the receptor
mediating binding of AGEs are harbored in the N-terminal V domain.
Among immunoglobulin superfamily members, the RAGE sequence is most
homologous to MUC 18 and the neural cell adhesion molecule.
After the extracellular region, there is a single
transmembrane-spanning domain and a short, highly charged cytosolic
tail at the C terminus. The latter portion of RAGE is most homologous
to the B cell activation marker CD20 and probably binds signal
transduction molecules in the cytoplasm to recruit cellular effector
mechanisms once ligand occupies the receptor. Placement of RAGE in the
immunoglobulin superfamily suggested that RAGE might participate
in the host response to environmental perturbation, as do cell
adherence molecules, rather than solely functioning as a scavenger of
modified polypeptides. Consistent with this concept, the
RAGE gene is on chromosome 6 in the major
histocompatibility complex between genes for class II and class
III.58 Furthermore, analysis of the RAGE
promoter shows putative nuclear factor-B (NF-B) sites, along with
an interferon-
response element and nuclear factor-interleukin 6 DNA
binding motif.59 We have analyzed the 3 NF-B
sites and found 2 of them to be active and involved in the regulation
of RAGE expression.59
Studies on human and rodent tissues have shown a characteristic pattern of RAGE expression.60 61 62 During development, the receptor is present at high levels, especially in the central nervous system. This led us to seek a ligand for RAGE of which the expression would be enhanced during development, an unlikely time for AGE formation. Amphoterin, a protein associated with basement membranes and abundant in the developing central nervous system,63 64 was found to bind RAGE.61 On amphoterin-coated matrices, RAGE mediates neurite outgrowth in primary cultures of rat cortical neurons. Furthermore, expression of RAGE and amphoterin in the developing rat brain is closely coordinated both temporally and spatially. Although these results do not establish a cause-effect relationship for amphoterin-RAGE interaction in the nervous system, they do suggest a role for RAGE under physiological conditions, rather than the unlikely possibility that RAGE participates solely in pathological events.
As animals mature, RAGE expression decreases to low levels in a range
of cells, including endothelium, smooth muscle cells,
mononuclear phagocytes, pericytes, neurons, cardiac myocytes,
hepatocytes, and Muller and bipolar ganglion cells of the
retina.61 However, when particular pathological processes
intervene, RAGE expression increases, and receptor upregulation can be
sustained, apparently over years. A striking feature of pathological
lesions characterized by an abundance of RAGE-expressing cells is the
almost invariable association with sites of accumulated RAGE
ligands. For example, in diabetic vasculature, cells expressing high
levels of RAGE are often proximal to areas in which AGEs are
abundant.52 62 A similar relationship has been shown in
affected vasculature from patients with Alzheimer disease, in
which RAGE functions as a cell surface receptor for Aß-mediating
cellular perturbation under conditions in which low (nanomolar) levels
of amyloidogenic material are present.65 66 In the
Alzheimer disease brain, RAGE is expressed in the vasculature
in proximity to deposits of Aß compared with age-matched controls
(Figure 1
). A molecular basis for these
immunohistological findings is suggested by the results
of our initial experiments analyzing regulatory elements in the RAGE
promoter; NF-B sites 1 and 2 are likely to have an important role in
ligand-associated upregulation of RAGE.59 We have found
that engagement of RAGE by AGEs or Aß results in activation of
NF-B,65 67 thereby triggering a positive feedback loop
in which increased RAGE expression enhances the capacity of the
cell for subsequent binding of AGEs/Aß. These events perpetuate
another cycle of increased receptor expression and cellular
perturbation. Such a mechanism stands out in sharp contrast to the
acute and self-limited host response to a burst of tumor necrosis
factor- production after exposure of cells to
lipopolysaccharide.2
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As a first test of the involvement of the AGE-RAGE axis in
vascular perturbation, the effect of RAGE on barrier function of
diabetic vasculature was studied. Increased vascular leakage is a
well-known feature of diabetic microvasculature68 69 70 71 72 and
is mirrored in rodent models of diabetes.19 73 Induction
of diabetes using the ß-cell toxin streptozotocin has been shown to
decrease insulin levels, resulting in a state analogous to type I or
insulin-dependent diabetes. By 10 to 11 weeks after administration of
streptozotocin, diabetic animals display increased vascular leakage, as
demonstrated by several methods, including the tissue-blood isotope
ratio.47 73 Increased vascular permeability in our
diabetic rats was most evident in intestine, skin, and kidney, in which
albumin leakage was increased 
2.8-fold, 3-fold, and
2.8-fold, respectively, compared with nondiabetic controls (Figure 2). Blockade of AGE-RAGE interaction was
accomplished using a truncated soluble form of the receptor, which we
have termed sRAGE, composed of only the extracellular domain
(V-C-C').47 In vitro, we have found that sRAGE binds up
AGEs and prevents their activation of the cell surface
receptor.37 47 Furthermore, sRAGE, either that prepared
from tissues or that produced using the baculovirus expression system,
was especially suitable for these and longer-term experiments: (1) it
was conveniently produced and purified to homogeneity in a
lipopolysaccharide-free form; (2) its half-time for elimination
from the plasma was 22 hours, allowing once-daily
intraperitoneal administration; and (3) sRAGE
occurs in normal plasma and, thus, is not a foreign species that
incites an immune response (even after several months of parenteral
administration). However, the low levels of RAGE in normal and diabetic
plasma (picogram range) are insufficient to antagonize AGE-RAGE
interaction. Diabetic rats were treated with a single dose of sRAGE,
2.25 or 5.15 mg/kg, resulting in plasma levels of sRAGE corresponding
to 10 to 30 and 40 to 60 µg/mL, respectively. Vascular
permeability studies were then performed using the tissue-blood isotope
ratio (Figure 2)47 ; sRAGE at the lower dose
completely blocked vascular leakage in intestine and skin and largely
prevented it in the kidney (60%). The higher dose of sRAGE
suppressed hyperpermeability completely in intestine and skin and by
90% in kidney. These data emphasize the contribution of a
reversible component of diabetic vascular dysfunction to
hyperpermeability in streptozotocin-treated diabetic rats at 10 weeks.
Furthermore, since administration of sRAGE reversed vascular leakage,
antagonism of AGE-RAGE interaction may be a relevant strategy for
preventing vascular dysfunction.
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RAGE and a Two-Hit Model of Vascular Perturbation
These data suggested a possible fundamental difference between
normal tissues and those tissues with abundant RAGE ligands, such as
AGEs or Aß. We have encapsulated these considerations into a 2-hit
model of vascular perturbation (Figure 3). AGE-rich tissues are populated by
cells expressing high levels of RAGE and are subject to sustained
AGE-RAGE interaction resulting in chronic cellular activation (see
below). The latter constitutes a chronic, underlying "first"
stimulus/hit in our model. We hypothesize that in AGE-enriched tissues
of diabetes, for example, superimposition of a second stress, such as
accumulated lipoproteins in atherosclerosis, results in
an exaggerated, chronic inflammation and accelerated
atherosclerosis, which are typical of diabetes. We
believe this concept can be extrapolated to the pathogenesis of other
pathological conditions related to diabetic complications, as well as
to consequences of amyloid angiopathy. Impaired wound healing in
diabetes extends this concept to the host response to acute tissue
damage, including the presence of a foreign body and introduction of
bacterial pathogens. In contrast to the rapid and transient triggering
of repair mechanisms in normal tissues, AGE-RAGE interaction introduces
a sustained and upwardly spiraling inflammatory component preventing
normal tissue repair from reaching completion. Cerebral amyloid
angiopathy involves vasculature rich in Aß and AGEs with high levels
of RAGE-bearing cells subject to repeated episodes of ischemia.
The likely impact of sustained RAGE activation in this setting is
enhanced severity of vascular and cerebral damage, as mechanisms to
limit the destructive host inflammatory response are suppressed and
repair cannot be consummated.
|
(red) indicates
macrophage.
The hypothesis outlined in Figure 3
led us to develop a model
system in which AGE-RAGE interaction was blocked in a setting of
ongoing vascular perturbation in an AGE-rich environment. Accelerated
atherosclerosis in patients with diabetes provided an
excellent arena to test this concept in view of its clinical
significance and the known role of additional risk factor(s), other
than hyperglycemia, hypertension, and
hyperlipidemias.8 9 10 11 12 However,
small-animal models mirroring macrovascular disease associated with
diabetes have been difficult to develop. For example, alloxan-induced
diabetic rabbits displayed protection from diet-induced
atherosclerosis probably as the result of accumulated
large triglyceride-rich lipoproteins in the plasma that
could not enter the vessel wall.74 The optimal choice
would be to use a rodent model, allowing exploitation of genetically
manipulated mice. However, previous studies have shown only enhanced
fatty streak formation in diabetic BALB/c versus strain-matched
euglycemic controls.75 For this reason, we
turned to atherosclerosis-prone mice, initially animals
with homozygous deletion of the apolipoprotein E (apoE)
gene,4 which had been backcrossed 10 times into the
C57BL/6J background to increase genetic homogeneity.76
Induction of diabetes was accomplished using streptozotocin. Within 7
weeks of streptozotocin administration, diabetic apoE-null animals
showed atherosclerosis of increased severity compared
with euglycemic apoE controls. Methylene blue–stained
preparations of mouse aortas demonstrated abundant lesions at aortic
branch points and the lesser curvature versus controls (Figure 4A and 4B). Quantitative analysis
of lesion formation showed 5.3-fold increased lesion area in
diabetic versus euglycemic apoE-null mice (Figure 5A). Microscopic examination of vascular
tissues displayed not only a more rapid time course for development of
vascular lesions in diabetic animals but also more complex lesions
(fibrous caps, extensive monocyte, smooth muscle infiltration, etc) and
atherosclerosis extending distally in the aorta and
major arteries. Increased expression of RAGE and the presence of AGEs
in the vessel wall, especially at sites of vascular lesions in diabetic
apoE-null animals, was evident. Although to a lesser extent than in
diabetic animals, nondiabetic apoE-null mice also showed increased
expression of the receptor and deposition of AGEs compared with
wild-type C57BL/6J. These data are consistent with the
previously noted occurrence of AGEs in vascular lesions from
atherosclerosis-prone hyperlipidemic
rabbits and in human vascular samples in the absence of
diabetes.24 28 29 30 77 The pro-oxidant environment
present in lipid-rich vascular lesions infiltrated by inflammatory
effector cells would appear sufficient to drive AGE formation in these
settings, as described above. It is important to emphasize that
vascular changes in streptozotocin-treated animals were not due to
toxic effects of this drug other than induction of diabetes. About 5%
of mice receiving streptozotocin did not become diabetic, although they
were treated with the same lot and dose of drug at the same time.
Atherosclerosis in these animals was identical to that
in apoE-null mice treated with vehicle alone; ie, it was not
accelerated as in the diabetic animals. Further support for the
generality of our observations concerns recent extension of our
findings to other genetically manipulated
atherosclerosis-prone mice and crossbreeding studies
into the genetically diabetic db/db background.78 79
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In view of the increased expression of RAGE in the vasculature of
diabetic apoE-null animals, along with the presence of AGEs, we used
sRAGE to interrupt the cycle of AGE engagement of RAGE potentially
underlying sustained cellular activation.76 Animals were
treated with several concentrations of sRAGE over a 6-week period after
the induction of diabetes, and dose-dependent reduction in lesion
formation to baseline (ie, vascular lesions observed in
euglycemic apoE-null mice) was observed (Figure 5A).
Analysis of aortas showed a striking suppression of lesions in
samples from diabetic apoE-null mice treated with sRAGE compared with
controls (Figure 5B and 5C). Lesions that did form in animals
receiving sRAGE appeared largely arrested at the fatty streak stage;
complex lesions were much less abundant than in
untreated/vehicle-treated diabetic apoE-null animals. Unexpectedly, the
tissue AGE burden in mice treated with sRAGE was also substantially
diminished (Figure 5D). This may represent attenuated
formation of AGEs and/or accelerated clearance of AGEs after formation
of sRAGE-AGE complexes. Such complexes could be detected by
immunoprecipitation in the plasma of animals treated with sRAGE.
Diminished AGE formation might be related to sRAGE-mediated suppression
of local oxidant stress by blocking RAGE-induced cellular activation
(see below). This would be consistent with the diminished
susceptibility to copper-induced oxidation of LDL retrieved from
sRAGE-treated diabetic apoE-null mice compared with LDL obtained from
control diabetic apoE-null mice.76
An important facet of the analysis of diabetic apoE-null
animals concerned the effect of diabetes and sRAGE treatment on the
lipoprotein profile and hyperglycemia. Induction of diabetes in mice
caused a 2-fold increase in total cholesterol, which was
mainly due to elevated levels of chylomicrons/VLDL and IDL/LDL, as
determined by ultracentrifugation, whereas
triglycerides were unchanged. Treatment of animals with
sRAGE had no effect on their cholesterol or
triglyceride levels and also resulted in no change in
glycemia or hemoglobin A1c. These studies
delineate a lipid- and glycemia-independent factor in diabetic
atherosclerosis due, at least in part, to AGE-RAGE
interaction.
RAGE-Induced Cellular Activation: Induction of Oxidant Stress
RAGE functions as a signal transduction receptor mediating
binding of AGEs and other ligands (see other sections of this review)
to the cell surface and activating intracellular signal transduction
mechanisms. One pathway of RAGE-dependent cellular perturbation
includes activation of p21ras, followed by
activation of mitogen-activated protein (MAP) kinases and
nuclear translocation of the transcription factor NF-B, resulting in
transcription of target genes.48 67 80 Binding of AGEs to
RAGE increases levels of GTP-bound p21ras within
10 minutes. Depletion of endogenous intracellular
glutathione with
L-buthionine-(S,R)-sulfoximine
enhanced p21ras activation consequent to AGE-RAGE
interaction, consistent with an oxidant stress–mediated
mechanism. The MAP kinases extracellular signal–regulated
kinases (ERKs) 1 and 2 are targets of activated
p21ras in cells exposed to AGEs; ERK1 and ERK2
activation peaked within 15 to 20 minutes. The close relationship of
p21ras activation to activation MAP kinases was
indicated by the inhibition of ERK1 and ERK2 activation in the presence
of the farnesyl transferase inhibitor
-hydroxyfarnesylphosphonic acid. Furthermore, when wild-type
p21ras was substituted for a mutant in which
cysteine present at residue 118, known to be a target of reactive
free radicals in p21ras,52
was replaced by serine, AGE-RAGE–dependent ERK1 and ERK2 activation
was blocked. Each of these events was closely tied to AGE binding to
RAGE, as blockade of the receptor with either anti-RAGE IgG or excess
sRAGE prevented NF-B activation. Additional evidence to support the
role of RAGE as a signaling molecule comes from our recent data
indicating that expression of a dominant negative form of RAGE (a
mutant lacking the cytosolic tail) prevents AGE-induced cellular
activation (A.M. Schmidt, S.D. Yan, and D. Stern, unpublished
observation, 1998). Furthermore, the principal AGE ligand of RAGE,
carboxymethyl-lysine adducts, appears to be biologically inert in the
absence of the receptor81 ; it does not generate
reactive oxygen species, it is not fluorescent, it does not
form cross-links, etc. Similar observations concerning RAGE-dependent
signal transduction have been made when Aß is the RAGE ligand.
Expression of NF-B–regulated genes is observed in pathological
samples in which RAGE and its ligands are present at high levels.
For example, increased expression of VCAM-1 and heme
oxygenase type I have been noted in diabetic
tissues.82 83 84 Infusion of AGEs into rodents enhances
expression of these cell stress markers in a RAGE-dependent manner and
is closely correlated with NF-B activation.48 67 In
Alzheimer disease, Aß engagement of RAGE on neurons leads to
expression of macrophage colony-stimulating factor (M-CSF), the
expression of which is also subject to regulation by
NF-B.67 Accordingly, Aß applied to neuron-like cells
induces activation of NF-B and expression of M-CSF in a
RAGE-dependent manner. The potential contribution of these mediators to
pathogenesis of chronic tissue injury can be easily suggested;
increased expression of VCAM-1 in diabetic vasculature would enhance
mononuclear phagocyte adherence to the vessel wall promoting
atherogenesis.85 86 Consistent with this
possibility, plasma levels of soluble VCAM-1 are increased in patients
with diabetes and microalbuminuria,87 the
latter of which is considered a harbinger of future vascular disease
(soluble VCAM-1 also correlated with atherogenesis in a more general
group of patients with non–insulin-dependent diabetes).88
In the setting of Alzheimer disease, M-CSF elaborated by
Aß-RAGE–stimulated neurons attracts and activates microglia
in the vicinity of Aß deposits, resulting in the elaboration of
potentially toxic mediators. Thus, activation of RAGE by either AGEs or
Aß can have serious consequences for sustained inflammation in
tissues.
Hypothesis
These data lead us to hypothesize that activation of RAGE occurs
in diverse circumstances using a repertoire of ligands. In the setting
of hyperglycemia, oxidant stress, renal failure, and amyloidosis,
glycoxidation causes formation and deposition of AGEs in the tissues
and vasculature. RAGE expression is enhanced, and the prolonged
proximity of AGEs to cells expressing RAGE sets the stage for sustained
cellular activation. Carboxymethyl-lysine adducts, produced by
glycoxidation, by oxidation alone, or in acute inflammation, may be an
important component of RAGE activation in each of these settings.
Alzheimer disease is another situation in which cells
expressing high levels of RAGE, neurons, microglia, and cells of the
vasculature are closely apposed to ligand, Aß, over long periods. In
addition, we have identified an inflammatory cytokine-like
molecule, termed EN-RAGE, which is elaborated by polymorphonuclear
leukocytes at inflammatory loci and which induces activation of
RAGE-bearing cells.89 In contrast to other host response
systems in which a negative feedback loop terminates cellular
activation, ligand engagement of RAGE appears to recruit cellular
effector mechanisms such as activation of NF-B, thereby enhancing
receptor expression and perpetuating cellular perturbation in an
ascending spiral. Taken together, these data suggest that intercepting
the vicious cycle of ligand-RAGE interaction will interrupt cellular
activation, potentially having a profound effect on a range of chronic
disorders. However, definitive proof that RAGE-dependent mechanisms
actually underlie the pathogenesis of human diseases must await more
direct experiments in mice, in which expression of RAGE has been
genetically manipulated, and in a range of higher species and humans
after the development of low molecular weight RAGE
inhibitors.
Although it is tempting to speculate that RAGE is optimally designed for molecular mischief in pathological states, it is essential to note that RAGE is likely to have important roles in discrete subsets of homeostasis as well. In adult rodents, antagonism of RAGE by administration of soluble receptor for up to 6 months has no adverse affects. This is consistent with the low levels of RAGE observed in tissues of mature animals in the absence of pathological processes. However, in development, high levels of RAGE are present in particular organ systems, especially the central nervous system. As noted previously, neurons expressing high levels of RAGE also produce amphoterin, another RAGE ligand. RAGE-dependent neurite outgrowth suggests a possible role of the receptor cell matrix interactions during normal development. Generation of RAGE knockout mice and targeted overexpression of dominant negative RAGE constructs should provide insights into such physiological functions of RAGE.
Acknowledgments
This work was supported by grants from the United States Public Health Service, Juvenile Diabetes Foundation, American Diabetes Association, Council for Tobacco Research, and American Heart Association (New York affiliate); by a generous gift from the Carrus Foundation; and by the Surgical Research Fund. Dr Gabriel Godman provided invaluable suggestions during the performance of this work and preparation of the manuscript.
Received August 18, 1998; accepted December 11, 1998.
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J. Asbun and F. J. Villarreal The Pathogenesis of Myocardial Fibrosis in the Setting of Diabetic Cardiomyopathy J. Am. Coll. Cardiol., February 21, 2006; 47(4): 693 - 700. [Abstract] [Full Text] [PDF]
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 R. De Caterina, A. Zampolli, S. Del Turco, R. Madonna, and M. Massaro Nutritional mechanisms that influence cardiovascular disease Am. J. Clinical Nutrition, February 1, 2006; 83(2): 421S - 426S. [Abstract] [Full Text] [PDF]
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 V. Schwenger, C. Morath, A. Salava, K. Amann, Y. Seregin, R. Deppisch, E. Ritz, A. Bierhaus, P. P. Nawroth, and M. Zeier Damage to the Peritoneal Membrane by Glucose Degradation Products Is Mediated by the Receptor for Advanced Glycation End-Products J. Am. Soc. Nephrol., January 1, 2006; 17(1): 199 - 207. [Abstract] [Full Text] [PDF]
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 M. Aragno, R. Mastrocola, C. Medana, F. Restivo, M. G. Catalano, N. Pons, O. Danni, and G. Boccuzzi Up-Regulation of Advanced Glycated Products Receptors in the Brain of Diabetic Rats Is Prevented by Antioxidant Treatment Endocrinology, December 1, 2005; 146(12): 5561 - 5567. [Abstract] [Full Text] [PDF]
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H. Koyama, T. Shoji, H. Yokoyama, K. Motoyama, K. Mori, S. Fukumoto, M. Emoto, T. Shoji, H. Tamei, H. Matsuki, et al. Plasma Level of Endogenous Secretory RAGE Is Associated With Components of the Metabolic Syndrome and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2587 - 2593. [Abstract] [Full Text] [PDF]
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 A. Lawrie, E. Spiekerkoetter, E. C. Martinez, N. Ambartsumian, W. J. Sheward, M. R. MacLean, A. J. Harmar, A.-M. Schmidt, E. Lukanidin, and M. Rabinovitch Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease Circ. Res., August 5, 2005; 97(3): 227 - 235. [Abstract] [Full Text] [PDF]
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 J. S. Jensen, B. Feldt-Rasmussen, K. Borch-Johnsen, K. S. Jensen, and B. G. Nordestgaard Increased Transvascular Lipoprotein Transport in Diabetes: Association with Albuminuria and Systolic Hypertension J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4441 - 4445. [Abstract] [Full Text] [PDF]
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R. Harris Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy: It's All the RAGE J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2251 - 2253. [Full Text] [PDF]
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 R. Pamplona, E. Dalfo, V. Ayala, M. J. Bellmunt, J. Prat, I. Ferrer, and M. Portero-Otin Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation: EFFECTS OF ALZHEIMER DISEASE AND IDENTIFICATION OF LIPOXIDATION TARGETS J. Biol. Chem., June 3, 2005; 280(22): 21522 - 21530. [Abstract] [Full Text] [PDF]
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C. Falcone, E. Emanuele, A. D'Angelo, M. P. Buzzi, C. Belvito, M. Cuccia, and D. Geroldi Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Artery Disease in Nondiabetic Men Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 1032 - 1037. [Abstract] [Full Text] [PDF]
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 E. D. Beishuizen, M. A. van de Ree, J. W. Jukema, J. T. Tamsma, J. C. M. van der Vijver, A. E. Meinders, H. Putter, and M. V. Huisman Two-Year Statin Therapy Does Not Alter the Progression of Intima-Media Thickness in Patients With Type 2 Diabetes Without Manifest Cardiovascular Disease Diabetes Care, December 1, 2004; 27(12): 2887 - 2892. [Abstract] [Full Text] [PDF]
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 A Heidland, K Sebekova, A Frangiosa, L S De Santo, M Cirillo, F Rossi, M Cotrufo, A Perna, A Klassen, R Schinzel, et al. Paradox of circulating advanced glycation end product concentrations in patients with congestive heart failure and after heart transplantation Heart, November 1, 2004; 90(11): 1269 - 1274. [Abstract] [Full Text] [PDF]
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 K. Kornerup, B. G. Nordestgaard, T. K. Jensen, B. Feldt-Rasmussen, J. P. Eiberg, K. S. Jensen, and J. S. Jensen Transendothelial exchange of low-density lipoprotein is unaffected by the presence of severe atherosclerosis Cardiovasc Res, November 1, 2004; 64(2): 337 - 345. [Abstract] [Full Text] [PDF]
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N. Marx, D. Walcher, N. Ivanova, K. Rautzenberg, A. Jung, R. Friedl, V. Hombach, R. de Caterina, G. Basta, M.-P. Wautier, et al. Thiazolidinediones Reduce Endothelial Expression of Receptors for Advanced Glycation End Products Diabetes, October 1, 2004; 53(10): 2662 - 2668. [Abstract] [Full Text] [PDF]
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 E. Selvin, S. Marinopoulos, G. Berkenblit, T. Rami, F. L. Brancati, N. R. Powe, and S. H. Golden Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes Mellitus Ann Intern Med, September 21, 2004; 141(6): 421 - 431. [Abstract] [Full Text] [PDF]
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A. Prasad and A. A. Quyyumi Renin-Angiotensin System and Angiotensin Receptor Blockers in the Metabolic Syndrome Circulation, September 14, 2004; 110(11): 1507 - 1512. [Full Text] [PDF]
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G. Basta, A. M. Schmidt, and R. De Caterina Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes Cardiovasc Res, September 1, 2004; 63(4): 582 - 592. [Abstract] [Full Text] [PDF]
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W. Cai, J. C. He, L. Zhu, M. Peppa, C. Lu, J. Uribarri, and H. Vlassara High Levels of Dietary Advanced Glycation End Products Transform Low-Density Lipoprotein Into a Potent Redox-Sensitive Mitogen-Activated Protein Kinase Stimulant in Diabetic Patients Circulation, July 20, 2004; 110(3): 285 - 291. [Abstract] [Full Text] [PDF]
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F. F. Hou, H. Ren, W. F. Owen Jr, Z. J. Guo, P. Y. Chen, A. M. Schmidt, T. Miyata, and X. Zhang Enhanced Expression of Receptor for Advanced Glycation End Products in Chronic Kidney Disease J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1889 - 1896. [Abstract] [Full Text] [PDF]
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 C. P Gale, T. S. Futers, and L. K. Summers Common polymorphisms in the glyoxalase-1 gene and their association with pro-thrombotic factors Diabetes and Vascular Disease Research, May 1, 2004; 1(1): 34 - 39. [Abstract] [PDF]
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 F. R. DANESH and Y. S. KANWAR Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy FASEB J, May 1, 2004; 18(7): 805 - 815. [Abstract] [Full Text] [PDF]
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S. V. Brodsky, O. Gealekman, J. Chen, F. Zhang, N. Togashi, M. Crabtree, S. S. Gross, A. Nasjletti, and M. S. Goligorsky Prevention and Reversal of Premature Endothelial Cell Senescence and Vasculopathy in Obesity-Induced Diabetes by Ebselen Circ. Res., February 20, 2004; 94(3): 377 - 384. [Abstract] [Full Text] [PDF]
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R. Marfella, C. Di Filippo, K. Esposito, F. Nappo, E. Piegari, S. Cuzzocrea, L. Berrino, F. Rossi, D. Giugliano, and M. D'Amico Absence of Inducible Nitric Oxide Synthase Reduces Myocardial Damage During Ischemia Reperfusion in Streptozotocin-Induced Hyperglycemic Mice Diabetes, February 1, 2004; 53(2): 454 - 462. [Abstract] [Full Text]
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B. Bouma, L. M. J. Kroon-Batenburg, Y.-P. Wu, B. Brunjes, G. Posthuma, O. Kranenburg, P. G. de Groot, E. E. Voest, and M. F. B. G. Gebbink Glycation Induces Formation of Amyloid Cross-{beta} Structure in Albumin J. Biol. Chem., October 24, 2003; 278(43): 41810 - 41819. [Abstract] [Full Text] [PDF]
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S. M. Culbertson, E. I. Vassilenko, L. D. Morrison, and Keith. U. Ingold Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation: COUNTERINTUITIVE INCREASE IN THE YIELDS OF PENTOSIDINE AND N{epsilon}-CARBOXYMETHYLLYSINE USING A NOVEL MULTIFUNCTIONAL PYRIDOXAMINE DERIVATIVE J. Biol. Chem., October 3, 2003; 278(40): 38384 - 38394. [Abstract] [Full Text] [PDF]
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M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I Circulation, September 23, 2003; 108(12): 1527 - 1532. [Full Text] [PDF]
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T. A. Ciulla, A. G. Amador, and B. Zinman Diabetic Retinopathy and Diabetic Macular Edema: Pathophysiology, screening, and novel therapies Diabetes Care, September 1, 2003; 26(9): 2653 - 2664. [Abstract] [Full Text] [PDF]
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X. JiXiong, X. BiLin, Y. MingGong, and L. ShuQin -429T/C and -374T/A Polymorphisms of RAGE Gene Promoter Are Not Associated With Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes Diabetes Care, September 1, 2003; 26(9): 2696 - 2697. [Full Text] [PDF]
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S. S. Shaw, A. M. Schmidt, A. K. Banes, X. Wang, D. M. Stern, and M. B. Marrero S100B-RAGE-Mediated Augmentation of Angiotensin II-Induced Activation of JAK2 in Vascular Smooth Muscle Cells Is Dependent on PLD2 Diabetes, September 1, 2003; 52(9): 2381 - 2388. [Abstract] [Full Text] [PDF]
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A. S. De Vriese, A. Flyvbjerg, S. Mortier, R. G. Tilton, and N. H. Lameire Inhibition of the Interaction of AGE-RAGE Prevents Hyperglycemia-Induced Fibrosis of the Peritoneal Membrane J. Am. Soc. Nephrol., August 1, 2003; 14(8): 2109 - 2118. [Abstract] [Full Text] [PDF]
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 K.-H. Mak and D. P. Faxon Clinical studies on coronary revascularization in patients with type 2 diabetes Eur. Heart J., June 2, 2003; 24(12): 1087 - 1103. [Abstract] [Full Text] [PDF]
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M. Morcos, A. A.R. Sayed, A. Bierhaus, B. Yard, R. Waldherr, W. Merz, I. Kloeting, E. Schleicher, S. Mentz, R. F. Abd el Baki, et al. Activation of Tubular Epithelial Cells in Diabetic Nephropathy Diabetes, December 1, 2002; 51(12): 3532 - 3544. [Abstract] [Full Text] [PDF]
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P. Libby and J. Plutzky Diabetic Macrovascular Disease: The Glucose Paradox? Circulation, November 26, 2002; 106(22): 2760 - 2763. [Full Text] [PDF]
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C. Napoli, L. O. Lerman, F. de Nigris, J. Loscalzo, and L. J. Ignarro Glycoxidized low-density lipoprotein downregulates endothelial nitricoxide synthase in human coronary cells J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1515 - 1522. [Abstract] [Full Text] [PDF]
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K. Esposito, F. Nappo, R. Marfella, G. Giugliano, F. Giugliano, M. Ciotola, L. Quagliaro, A. Ceriello, and D. Giugliano Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress Circulation, October 15, 2002; 106(16): 2067 - 2072. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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A. E. Mullick, J. M. McDonald, G. Melkonian, P. Talbot, K. E. Pinkerton, and J. C. Rutledge Reactive carbonyls from tobacco smoke increase arterial endothelial layer injury Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H591 - H597. [Abstract] [Full Text] [PDF]
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K. Kornerup, B. G. Nordestgaard, B. Feldt-Rasmussen, K. Borch-Johnsen, K. S. Jensen, and J. S. Jensen Transvascular Low-Density Lipoprotein Transport in Patients With Diabetes Mellitus (Type 2): A Noninvasive In Vivo Isotope Technique Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1168 - 1174. [Abstract] [Full Text] [PDF]
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K. C.B. Tan, W.-S. Chow, V. H.G. Ai, C. Metz, R. Bucala, and K. S.L. Lam Advanced Glycation End Products and Endothelial Dysfunction in Type 2 Diabetes Diabetes Care, June 1, 2002; 25(6): 1055 - 1059. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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M. Perera, J.R. Petrie, C. Hillier, M. Small, N. Sattar, J.M.C. Connell, and M.A. Lumsden Hormone replacement therapy can augment vascular relaxation in post-menopausal women with type 2 diabetes Hum. Reprod., February 1, 2002; 17(2): 497 - 502. [Abstract] [Full Text] [PDF]
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A. Bierhaus, S. Schiekofer, M. Schwaninger, M. Andrassy, P. M. Humpert, J. Chen, M. Hong, T. Luther, T. Henle, I. Kloting, et al. Diabetes-Associated Sustained Activation of the Transcription Factor Nuclear Factor-{kappa}B Diabetes, December 1, 2001; 50(12): 2792 - 2808. [Abstract] [Full Text] [PDF]
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A. E. Mullick, B. A. Walsh, K. M. Reiser, and J. C. Rutledge Chronic estradiol treatment attenuates stiffening, glycoxidation, and permeability in rat carotid arteries Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2204 - H2210. [Abstract] [Full Text] [PDF]
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T. Kislinger, N. Tanji, T. Wendt, W. Qu, Y. Lu, L. J. Ferran Jr, A. Taguchi, K. Olson, L. Bucciarelli, M. Goova, et al. Receptor for Advanced Glycation End Products Mediates Inflammation and Enhanced Expression of Tissue Factor in Vasculature of Diabetic Apolipoprotein E-Null Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 905 - 910. [Abstract] [Full Text] [PDF]
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C.-H. Yeh, L. Sturgis, J. Haidacher, X.-N. Zhang, S. J. Sherwood, R. J. Bjercke, O. Juhasz, M. T. Crow, R. G. Tilton, and L. Denner Requirement for p38 and p44/p42 Mitogen-Activated Protein Kinases in RAGE-Mediated Nuclear Factor-{kappa}B Transcriptional Activation and Cytokine Secretion Diabetes, June 1, 2001; 50(6): 1495 - 1504. [Abstract] [Full Text]
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B. I. Hudson, M. H. Stickland, T. S. Futers, and P. J. Grant Effects of Novel Polymorphisms in the RAGE Gene on Transcriptional Regulation and Their Association With Diabetic Retinopathy Diabetes, June 1, 2001; 50(6): 1505 - 1511. [Abstract] [Full Text]
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S. M. Twigg, M. M. Chen, A. H. Joly, S. D. Chakrapani, J. Tsubaki, H.-S. Kim, Y. Oh, and R. G. Rosenfeld Advanced Glycosylation End Products Up-Regulate Connective Tissue Growth Factor (Insulin-Like Growth Factor-Binding Protein-Related Protein 2) in Human Fibroblasts: A Potential Mechanism for Expansion of Extracellular Matrix in Diabetes Mellitus Endocrinology, May 1, 2001; 142(5): 1760 - 1769. [Abstract] [Full Text]
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S. G. ROSTAND Coronary Heart Disease in Chronic Renal Insufficiency: Some Management Considerations J. Am. Soc. Nephrol., October 1, 2000; 11(10): 1948 - 1956. [Full Text]
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S. D. Yan, A. Roher, A. M. Schmidt, and D. M. Stern Cellular Cofactors for Amyloid {beta}-Peptide-Induced Cell Stress : Moving from Cell Culture to in Vivo Am. J. Pathol., November 1, 1999; 155(5): 1403 - 1411. [Full Text] [PDF]
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N. Tanaka, H. Yonekura, S.-i. Yamagishi, H. Fujimori, Y. Yamamoto, and H. Yamamoto The Receptor for Advanced Glycation End Products Is Induced by the Glycation Products Themselves and Tumor Necrosis Factor-alpha through Nuclear Factor-kappa B, and by 17beta -Estradiol through Sp-1 in Human Vascular Endothelial Cells J. Biol. Chem., August 11, 2000; 275(33): 25781 - 25790. [Abstract] [Full Text] [PDF]
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