Keywords
advanced glycation end products (AGE) - cell receptor for AGE - soluble receptors
AGE - coronary artery disease (CAD) - atherosclerosis - atherosclerotic plaque rupture
- AGE–RAGE stress - treatment modalities for AGE-RAGE stress-induced CAD
Coronary artery disease (CAD), also known as coronary heart disease (CHD), and ischemic
heart disease are due to reduced blood supply to the heart. Coronary artery stenosis
manifests in clinical syndrome called stable angina and acute coronary syndrome (ACS).
Acute coronary syndrome includes unstable angina and ACS (ST-segment elevated myocardial
infarction [STEMI], and non-ST-segment elevated myocardial infarction [NSTEMI]).[1] Although ACS, CHD, and CAD are used interchangeably, they are not the same. ACS
is the subcategory of CAD, while CHD is the result of CAD. According to World Health
Organization, CAD is the main cause of death globally (>9 million death in 2016).[2] Russia, United States, Ukraine, Germany, and Brazil had the most number of death
due to CAD in 2015.[3] They also reported that mortality has progressively decreased from 2005 to 2015.
Fifty percent of all death from cardiovascular disease (CVD) is due to CAD.[4] CAD is due to atherosclerosis. As atherosclerosis progresses, atherosclerotic plaques
rupture resulting in arterial occlusion or dislodged material from plaques blocking
the smaller branches of coronary artery. The risk factors for atherosclerosis or CAD
include dyslipidemia,[5]
[6] diabetes,[7] hypertension,[8] cigarette smoking,[9]
[10] obesity,[10] hyperhomocysteinemia,[11] and C-reactive protein.[12] Advanced glycation end products (AGE) and its cell receptors RAGE (receptor for
AGE), and soluble receptors sRAGE (soluble receptor for AGE) and esRAGE (endogenous
secretory receptor for AGE) have been implicated in various diseases including, NSTEMI,[13] restenosis following percutaneous coronary intervention (PCI),[14] carotid artery de-endothelialization-induced neointima expansion in wild-type mice,[15]
[16] streptozotocin-induced diabetes accelerated atherosclerosis in apo-E-deficient mice,[17] and accelerated atherosclerosis in apoE-deficient mice.[18] This chapter addresses the RAGE stress and the role of AGE–RAGE stress in the pathogenesis
of atherosclerosis, AGE, RAGE, and sRAGE levels in patients with CAD and the treatment
strategy for prevention, regression, and slowing of the progression of CAD.
AGE–RAGE Stress
AGEs are heterogenous groups of irreversible adducts produced by nonenzymatic glycation
and glycoxidation of proteins, nucleic acid with reducing sugars.[19]
[20] There are four receptors for AGE: full length cell receptor for AGE (RAGE), N-truncated
RAGE, and two C-truncated RAGE. Interaction of AGE with RAGE has adverse effects on
cell function and initiates and accelerate the progression of various diseases. This
will be discussed in detail in a section on atherogenic effects of AGE and its interaction
with RAGE. N-truncated RAGE is bound in the plasma membrane, but its function is not
well understood as yet. C-truncated RAGE has two isoforms, cleaved RAGE (c-RAGE),
and endogenous secretory RAGE (esRAGE). c-RAGE is proteolytically cleaved from full
length RAGE,[21] while esRAGE is produced from alternative mRNA splicing of full-length RAGE.[22] c-RAGE and esRAGE lack cytosolic and transmembrane domain and circulate in the blood.
sRAGE comprises of both c-RAGE and esRAGE. Twenty to thirty percent of sRAGE is esRAGE.[23]
[24] sRAGE binding with ligands does not activate intracellular signaling. Both sRAGE
and esRAGE compete with RAGE for ligand binding and thus have protective effects against
adverse effects of AGE-RAGE binding. Prasad and Mishra[25] have coined three terminologies in the AGE–RAGE axis that comprises of AGE, RAGE,
and sRAGE. AGE and its interaction with RAGE have been coined as stressors because
they produce adverse effects. The agents that reduce the adverse effects of AGE and
its interaction with RAGE have been coined as antistressors that include endogenous,
exogenous, and down regulation of RAGE expression. Endogenous antistressors include
enzymatic degraders of AGE (glyoxalase-1, glyoxalase-2), AGE receptor–mediated degraders
of AGE (AGE receptor-1 [AGER-1], AGER-2), and sRAGE. Exogenous antistressors include
reduction in AGE consumption and exogenous administration of sRAGE. AGE–RAGE stress
has been defined as a shift in balance between stressors and antistressors in favor
of stressors.[25] Prasad and Mishra[25] have constructed a formula to assess AGE–RAGE stress. The ratio of AGE/sRAGE has
been proposed as a simple and feasible measure of AGE–RAGE stress in clinical practice.
A high index of AGE–RAGE stress would initiate the development and progression of
diseases including CAD.
Atherogenic Effects of AGE–RAGE Stress
Atherogenic Effects of AGE–RAGE Stress
AGE–RAGE stress could produce atherosclerosis in two ways: direct effect of AGE and
interaction of AGE with RAGE.
Direct Effects of AGE
AGE modifies apoB100 that makes low-density lipoprotein (LDL) more atherogenoic.[26] Glycation of apoB and phospholipid component of LDL alters the LDL clearance and
increases the susceptibility of LDL oxidation.[27]
[28] Glycated LDL decreases its recognition by LDL receptors,[29] and increases smooth muscle cell proliferation and differentiation.[30]
[31] AGE interferes with reverse cholesterol transport[29] resulting in extracellular accumulation of cholesterol. AGE enhances accumulation
of cholesterol and its esters in macrophages in vitro.[32] AGE increases synthesis of extracellular matrix[33] and cross-binds with collagen.[34] Cross-linking of AGE with collagen and elastin enhances arterial stiffness.[35] Matrix-bond AGE increases expression of endothelin-1[36] that has been suggested to be involved in the development of atherosclerosis.[33] Generation of nitric oxide (NO) is reduced by AGE[37] and oxidized LDL.[38] AGE quenches NO[39] and matrix-bond AGE quenches and inactivates NO.[40] Matrix-bond AGE inhibits antiproliferative activity of NO.[41] In summary, the above data suggest that AGE initiates and helps in progression of
atherosclerosis through LDL oxidation, interfering reverse cholesterol transport,
altering LDL clearance, increasing smooth muscle cell proliferation and differentiation,
increasing expression of endothelin and extracellular matrix, reducing generation
of NO, and quenching and inactivation of NO.
Effects of Interaction of AGE with RAGE
Effects of Interaction of AGE with RAGE
AGE interacts with RAGE to produce reactive oxygen species (ROS)[42] that activates nuclear factor kappa-B (NF-kB) that in turn activates numerous proinflammatory
genes of cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-2,
IL-6, IL-8, IL-9.[43]
[44] Interaction of AGE with RAGE increases expression of intercellular adhesion molecule-1
(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin.[45] ROS itself upregulates the expression of ICAM-1, VCAM-1, and endothelial leucocytes
adhesion molecules.[46]
[47]
[48] AGE increases expression of monocyte chemoattractant protein-1 (MCP-1) in mesangial
cells,[49] and MCP-1 and vascular endothelial growth factor in human-cultured mesangial cells.[50] Expression and secretion of granulocyte macrophage-colony stimulating factor (GM-CSF)
by macrophages is enhanced with AGE.[51] AGE–RAGE interaction enhances expression of insulin-like growth factor-1 and platelet-derived
growth factor (PDGF).[52] AGE enhances the expression of transforming growth factor-β.[53] These data suggest that AGE–RAGE interaction enhances the expression of biomolecules
required for initiation and progression of atherosclerosis. It also implies that sRAGE
is protective against AGE–RAGE-induced atherosclerosis.
Mechanisms Involved in AGE–RAGE Stress-Induced Atherosclerosis and Plaque Rupture
Mechanisms Involved in AGE–RAGE Stress-Induced Atherosclerosis and Plaque Rupture
AGE and its interaction with RAGE-induced atherogenic biomolecules have been implicated
in atherosclerosis and have been described in detail by Prasad[9] and Prasad and Bhanumathy.[54] Most of the ACS is associated with plaque rupture.[55]
[56] Matrix metalloproteinases (MMPs) have been implicated in plaque rupture. There is
overexpression of MMPs in atherosclerotic lesions. An increased expression of MMP1
in several cell types in human carotid atherosclerotic plaques and its correlation
with histopathological evidence of plaque instability have been reported by Nikkari
et al.[57] MMP-9 has been reported to be elevated in atherectomy specimen from patients with
unstable angina.[58] IL-1, PDGF, and TNF-α have been shown to stimulate expression of MMPs.[59]
[60]
[61] Oxidative stress increases the expression of MMP-1 and MMP-3.[62]
[63] ROS may be involved in stability of atherosclerotic plaques.[64] The above data also suggest that AGE and its interaction with RAGE may be involved
in the instability and rupture of atherosclerotic plaque and ACS.
Serum Levels of AGE, RAGE, sRAGE, esRAGE, and AGE–RAGE Stress in Patients with CAD
Serum Levels of AGE, RAGE, sRAGE, esRAGE, and AGE–RAGE Stress in Patients with CAD
If AGE–RAGE stress is involved in the pathophysiology of CAD, then the serum levels
of AGE, RAGE, and AGE/sRAGE should be elevated while the levels of sRAGE and esRAGE
would be reduced. The following section would deal with the serum levels of AGE, RAGE,
sRAGE, esRAGE, and AGE/sRAGE in patients with CAD.
Serum Levels of AGE in Patients with CAD
Serum Levels of AGE in Patients with CAD
Levels of AGEs have been measured in serum/plasma and skin autofluorescence in patients
with CAD. Skin autofluorescence is a noninvasive measurement of levels of AGE in skin.[65] Serum levels of AGE are elevated in CAD patients with type2 diabetes as compared
with CAD patients without diabetes.[66] Kilhovd et al[67] measured the serum levels of AGEs in 1141 nondiabetic individuals at base line and
followed up for 18 years. Eighty-four patients died of CAD during this follow-up period
and the death was associated with elevated levels of serum AGE. The data suggest that
serum levels of AGE can predict CHD mortality in nondiabetic women but not in nondiabetic
men. Kanauchi et al[68] measured serum levels of AGE in nondiabetic patients with significantly stenosed
vessels assessed by coronary angiography, and found that serum levels of AGEs were
significantly higher in nondiabetic subjects with CAD than in control subjects and
were significantly correlated with number of significantly stenosed vessels. The levels
of AGEs were significantly higher in group with three vessels disease than in group
with zero and 1 vessel disease. McNair et al[13] have reported that the serum levels of AGE were higher in NSTEMI subjects compared
with control subjects. The also showed that the levels AGE were higher to similar
extent in patients with 1 vessel, 2 vessels, and 3 vessels disease compared with control
subjects. McNair et al[14] reported that the serum levels of AGE pre-PCI were higher in patients of both groups
who developed or did not develop post-PCI restenosis but the post-PCI levels of AGE
were significantly higher in patients who developed post-PCI restenosis compared with
control subjects. Serum AGE levels are elevated in patients undergoing PCI and is
reported to be an independent risk factor for restenosis in diabetic patients.[69] Serum levels of AGE were elevated in type 2 diabetic patients with obstructive CAD
compared with diabetics with nonobstructive CAD and levels of AGE correlated with
degree of coronary artery atherosclerosis.[70] This association was independent of other risk factors for CAD including hypertension,
cigarette smoking, hyperlipidemia, and hyperuricemia. Serum levels of AGE have been
suggested to be a biomarker for severity of coronary artery atherosclerosis in type
2 diabetic patients independent of hypertension, hyperlipidemia, and cigarette smoking.[71] Kerkeni et al[72] have reported that there was an association between elevated levels of pentosidine
(a type of AGE) and obstructive CAD and its severity was independent of diabetes.
Plasma levels of AGEs like carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL),
pentosidine, and tetrahydropyrimidine (THP) were elevated in diabetic patients.[73] Higher levels of plasma pentosidine but not CML, CEL, and THP were associated with
moderate-to-high coronary artery calcium score compared with a low coronary artery
calcium score in type 1 diabetic patients. An association between higher CML and cardiovascular
mortality has been reported in a prospective study of over 1,000 patients over 65
years of age and followed for a median time of 6 years.[74] Lu et al[75] in a cross-section study showed that the serum levels of glycated albumin were significantly
elevated in patients with both type 2 diabetes and significant CAD. They also reported
that there was no significant difference in glycated albumin levels in nondiabetic
patients with or without CAD. Glycated albumin levels were associated with angiographic
CAD severity, extent and number of diseased coronary arteries in diabetic CAD patients.
Serum levels of AGE were significantly elevated in diabetic patients with CHD as compared
with those without CHD.[76]
In some studies, AGE levels were measured with skin autofluorescence and the results
were similar to that measured with immunoassay in CAD patients. Mulder et al[77] reported that skin autofluorescence is elevated in patients with stable CAD compared
with healthy control. Yozgatli et al[78] have shown that there was a correlation between increased levels of skin autofluorescence
and CAD independent of hemoglobin A1c levels in type 2 diabetic patients. Conway et
al[79] elevated skin autofluorescence was associated with severity of coronary artery calcium
score in type1 diabetics. There was no significant difference in skin autofluorescence
among unstable angina, NSTEMI, and STEMI at admission. However, AGE levels increased
significantly in patients with cardiac events during follow-up.[80] It has been reported that increased levels of AGE in patients with diabetes accelerate
the development and progression of heart failure both indirectly through coronary
dysfunction and atherosclerosis,[81] and directly through its action on myocardiam.[82] In summary, the serum levels of AGE are elevated in patients with CAD.
Serum Levels of sRAGE in CAD Patients
Serum Levels of sRAGE in CAD Patients
There are conflicting reports about the use of sRAGE as a biomarker for CVD. Selvin
et al[83] measured the plasma levels of sRAGE in 1201 participants who had normal kidney function,
and no history of CVD, and followed up for 18 years. They found that during that period
192 (16%) participants developed CAD events that was associated with low levels of
plasma sRAGE suggesting that low sRAGE levels were biomarker of future chronic CAD.
Falcone et al[84] measured the plasma levels of sRAGE in 328 nondiabetic patients with angiographically
proven CAD and 328 age-matched healthy control and showed that low plasma levels of
sRAGE were independently associated with CAD in nondiabetic individuals. It has been
reported that plasma levels of sRAGE were significantly lower in patients with ACS
(unstable angina and myocardial infarction) than in patients with stable angina.[85] They also reported that the plasma levels of sRAGE were not affected by statin therapy,
number of diseased vessels, and extent of coronary disease. Other investigators[84]
[85]
[86]
[87] have also reported reduced plasma levels of sRAGE in patients with ACS and stable
angina when compared with control subjects. It has been reported that plasma levels
of sRAGE were significantly lower in patients with CAD with or without peripheral
vascular disease (PVD) compared with control.[88] They also showed that CAD patients with PVD had lower plasma sRAGE compared with
those without PVD. Low levels of serum sRAGE in patients with suspected CAD were predictive
of cardiovascular events after follow-up for 48 months.[89] Low levels of sRAGE have been reported to be associated with high coronary calcium
score.[90] Serum levels of sRAGE have been reported to be lower in NSTEMI patients compared
with control subjects.[13] Pre-PCI levels of serum sRAGE were significantly lower in NSTEMI patients who developed
or not developed post-PCI restenosis compared with control subjects; however, the
levels of sRAGE were significantly lower in patients who developed restenosis compared
with those who did not develop restenosis.[14] Pre- and post-PCI levels of sRAGE in NSTEMI patients were similar who did not develop
restenosis following PCI. On the other hand, post-PCI levels of sRAGE were significantly
lower than those who developed restenosis.[14] McNair et al[13] have shown that sRAGE levels were inversely associated with number of stenosed vessels.
McNair et al[91] also reported that levels of sRAGE were lower in NSTEMI patients compared with control
and that there was a negative correlation between sRAGE and cardiac troponin-I (cTnI).
However, there are numerous papers showing increases in the serum levels of sRAGE
in patients with CAD. It has been reported that plasma levels of sRAGE were higher
in patients with NSTEMI-ACS than in patients with stable angina and positively correlated
with cTnI.[92] Nakamura et al[93] have shown that serum levels of sRAGE were significantly higher in diabetic patients
with CAD than in diabetic patients without CAD. sRAGE levels are directly corelated
with presence and severity of CAD in patients with and without diabetes.[70]
[94]
[95]
[96] Wang et al[97] measured the plasma levels of sRAGE in patients with normal coronary artery, nonobstructive
coronary artery (< 50% stenosed coronary artery), stable angina and ACS, and observed
that plasma levels of sRAGE were higher compared with control group, nonobstructive
coronary artery, and stable angina group. The levels did not change significantly
in patients with stable angina and nonstenosed coronary artery compared with control
subjects. They concluded that the elevated levels of sRAGE may be independently associated
with severity of CAD and inflammation. It would have been useful to measure the plasma
levels of AGE. It is possible that plasma levels of AGE are also elevated, and its
elevation is greater than the elevation of sRAGE in these patients resulting in an
increase in the ratio of AGE/sRAGE and hence adverse effects on coronary artery. They
have measured S100A12 a ligand for sRAGE. However, they did not provide the ratio of S10012/sRAGE. Increase in the ratio of AGE/sRAGE has been reported to be risk factor/biomarker
for diseases.[25]
[98] Park et al[96] have reported that plaque vulnerability was associated with increased levels of
plasma sRAGE and MMP-9 in patients with acute myocardial infarction compared with
control subjects. sRAGE is a protective biochemical and hence its increased levels
should not be responsible for plaque vulnerability. Also increased levels of sRAGE
are known to decrease the levels MMPs.[99]
[100] It is also possible that that AGE levels are elevated and the elevation is greater
than sRAGE increasing the ratio of AGE/sRAGE that would increase the MMP levels.[99] It is known that AGE–RAGE interaction increases the generation of MMP-9 that in
turn would produce plaque rupture. MMP-9 has been implicated in plaque rupture.[57]
[58] Raposeiras-Roubín et al[80] have reported that there were no significant differences in skin autofluorescence
AGE and plasma sRAGE among unstable angina, STEMI and NSTEMI subjects at admission
in the hospital. However, cardiac events (cardiac deaths, reinfarction, and new onset
of heart failure) were associated with increased levels of sRAGE. In summary, serum
levels of sRAGE were reduced in most patient but were elevated in some patients with
CAD.
Serum Levels of esRAGE in CAD Patients
Serum Levels of esRAGE in CAD Patients
Wagner et al[101] have reported that low plasma levels of esRAGE were associated with increased CV
mortality, suggesting that esRAGE is better predictive marker than cRAGE alone. Increased
levels of AGE and decreased levels of esRAGE are associated with angiographic severity
and extent of CAD in patients with type 2 diabetes.[75] Lu et al[102] have shown that increased AGE and decreased esRAGE are associated with in-stent
restenosis in Chinese diabetic patients. Elevated levels of serum AGE and reduced
levels of serum sRAGE and esRAGE are associated with severity of albuminuria and postprocedural
contrast-induced acute kidney injury, and exert a negative impact on 1-year clinical
outcome in patients with type 2 diabetes undergoing PCI with Sirolimus-eluting stent
implantation.[103] Yang et al[104] have reported that lower serum levels of esRAGE were associated with higher major
cardiovascular events in patients with type 2 diabetes and stable CAD undergoing PCI.
Serum levels of esRAGE are lower in patients with angiographically determined coronary
plaque progression in diabetic patients,[105] and in subjects with greater atherosclerosis burden than control subjects.[24]
[105]
[106] Serum esRAGE has been reported to be lower in patients with type 2 diabetes and
CAD compared with control subjects, while there was no significant difference the
these levels in patients with CAD in nondiabetic patients and control subjects.[75] However, Colhoun et al[107] reported an elevated levels of serum esRAGE in patients with CAD. The above data
suggest that the serum levels of esRAGE are reduced in patients with CAD with one
exception. In summary, serum levels of esRAGE were lower in both the diabetic and
nondiabetic patients with CAD.
Expression of RAGE in CAD Patients
Expression of RAGE in CAD Patients
Expression of RAGE in coronary artery of CAD patients is not available in literature.
However, Rodiño-Janeiro et al[108] have shown that RAGE expression in subcutaneous adipose tissue but not in epicardial
adipose tissue is downregulated in patients with CAD as compared with those without
CAD. RAGE expression is upregulated in atherosclerotic lesion. Expression of RAGE
is elevated in carotid arterial wall of Zucker diabetic rats as compared with euglycemic
control rats and the levels are further elevated in balloon-injured carotid artery
of these rats.[15] Arterial de-endothelialization in wild-type mice increases the expression of RAGE
in injured vessels.[16] Expression of RAGE in apoE −/− mice is significantly increased in atherosclerotic
plaque.[109] These investigators also reported that the development of atherosclerosis was prevented
in double knockout (apoE −/− /RAGE −/− ) diabetic mice. In apoE −/− and RAGE −/− (double
knockout) mice, the plaque area is reduced.[110] Forbes et al[111] reported that the expression of RAGE is focally increased in atherosclerotic vascular
disease. Blockade of RAGE expression with sRAGE or genetically RAGE deleted mice protected
the ischemia-reperfusion myocardial injury[112]
[113] In summary, RAGE expression was upregulated in atherosclerotic lesions in animal
model of atherosclerosis and blockade of RAGE expression with sRAGE or genetically
RAGE deletion (RAGE −/−) prevented the development of atherosclerosis and ischemia reperfusion cardiac injury
in mice. These data suggest that RAGE is involved in the genesis of atherosclerosis.
AGE–RAGE Stress in CAD
There are limited reports on the AGE–RAGE stress in patients with CAD. McNair et al[13] measured the ratio of AGE/sRAGE (AGE–RAGE stress) in 46 men with NSTEMI and 28 control
subjects and observed that AGE/sRAGE ratio were significantly higher in patients with
NSTEMI compared with control subjects. They also reported that the ratio of AGE/sRAGE
was significantly elevated to a similar degree in NSTEMI with 1 vessel, 2 vessels,
and 3 vessels disease when compared with control subjects. McNair et al[14] investigated if post-PCI restenosis is associated with high AGE/sRAGE ratio and
if pre-PCI and post-PCI levels of AGE/sRAGE were similar in patients with or without
post-PCI restenosis in NSTEMI patients. They reported that pre-PCI ratio of AGE/sRAGE
was greater in both groups of patients who developed or did not develop post-PCI restenosis
as compared with control subjects, but the increases were more in post-PCI patients
who developed restenosis than those who did not develop restenosis.
Hyperlipidemia is a risk factor for CAD. We[114] investigated if hyperlipidemia is associated with increased levels of AGE/sRAGE
in 100 patients with NSTEMI and observed that there was a positive correlation of
AGE/sRAGE with total cholesterol, triglycerides, and LDL-C levels, and negative correlation
between HDL-C and AGE/sRAGE. Kazikawa et al[115] measured the endothelial cell dysfunction using flow mediated and nitroglycerine
induced-vasodilation and AGE–sRAGE ratio in 110 subjects and concluded that AGE/sRAGE
is an independent predictor of endothelial dysfunction. Endothelial dysfunction is
precursor for atherosclerosis. The above data suggest that AGE–RAGE stress is involved
in the CAD.
Evidence for AGE–RAGE Stress-Induced Atherosclerosis
Evidence for AGE–RAGE Stress-Induced Atherosclerosis
Evidences suggest that AGE–RAGE stress is involved in the development of atherosclerosis.
AGE and RAGE levels are elevated in carotid arterial wall of Zucker diabetic rats
as compared with euglycemic control rats and the levels of AGE and RAGE are further
elevated in the balloon-injured carotid artery of these rats.[15] Administration of sRAGE before and for up to 21 days post-balloon injury significantly
reduced neointimal hyperplasia and this was associated with decreases in vascular
smooth muscle cell growth in vitro and vascular smooth muscle cell proliferation in
vivo in these rats. Arterial de-endothelialization in wild-type mice increases the
expression of RAGE in injured vessel, especially in smooth muscle cells, and increases
deposition of AGE in expanding intima.[16] They demonstrated that administration sRAGE decreased neointimal hyperplasia, smooth
muscle cell proliferation and migration, and expression of extracellular matrix protein.
Atherosclerosis is accelerated in streptozotocin-induced diabetes in apoE-deficient
mice and this effect was associated with increased expression of VCAM-1 in aorta when
compared with nondiabetic mice.[17] These investigators also reported that administration of sRAGE significantly decreased
the atherosclerotic lesion in a glycemic-and lipid-independent manner. Expression
of RAGE and VCAM-1 was elevated in aorta of apo-E deficient diabetic rats and that
expression of RAGE and VCAM-1 was downregulated with administration of sRAGE.[116] sRAGE has been reported to completely suppress accelerated and advanced atherosclerosis
in apoE-deficient mice.[18] McNair et al[13] have reported that sRAGE levels are reduced in patients with NSTEMI. McNair et al[14] have also shown that reduced serum levels of sRAGE are a predictor of restenosis
following PCI. Prasad[117] has discussed in detail the role of AGE and RAGE in the development and progression
of carotid artery stenosis. AGE–RAGE axis may also play a role in the development
of CAD.[118] It is to note that ROS also depresses myocardial contractility.[119] This effect of ROS would add to the cardiac effects of atherosclerosis. ROS is involved
in the development of atherosclerosis.[120]
[121]
[122]
Treatment Modalities for AGE–RAGE Stress-Induced CAD
Treatment Modalities for AGE–RAGE Stress-Induced CAD
Considering the involvement of AGE–RAGE axis in genesis of atherosclerosis (CAD),
the treatment target should include reduction in AGE, RAGE, and ROS levels, degradation
of AGE in vivo, blocking of AGE–RAGE binding, and elevation of sRAGE. The treatment
modalities for AGE–RAGE-induced diseases have been described in detail by Prasad and
Tiwari[123] and Prasad and Bhanumathy.[54] A brief description of treatment of CAD is outlined below.
-
AGE-reduction
AGE reduction in the body can be achieved by reduction in AGE intake, modification
in food cooking, and other AGE lowering procedures.
-
Intake of AGE
AGE levels in the body can be lowered by reducing intake of food containing high amount
of AGE (red meat, animal fat, cheese, and sweetened food).[124] The use of food such as grains, legumes, breads, vegetables, fruits, and low-fat
milk that contain lowest amount of AGE[125] should be encouraged.
-
Food cooking
Cooking of food at low temperature in moist heat for short duration should be advised,
because it reduces the formation of AGE.[125] Cooking at high temperature in dry heat (frying, broiling, grilling and roasting)
increases formation of AGE.[125]
-
Other AGE lowering procedures
Cigarette smoking should be stopped because it increases the serum levels of AGE.[126] Exercise should be advocated because exercise reduces the AGE levels.[127]
[128] Sugar consumption should be reduced because it increases the formation of AGE.[19]
[20]
-
Reduction in AGE formation
AGE formation can be reduced with vinegar, lemon juice, benfotiamine, pyridoxine,
vitamins C, D and E, α-lipoic acid, resveratrol, and curcumin.[54]
[123]
-
Suppression of RAGE expression
RAGE expression is suppressed with the use of statins, candesartan, nifedipine, and
rosiglitazone.[54]
[117]
-
RAGE receptor blocker
Azeliragon has been used for AGE receptor blocker in patients with Alzheimer's disease.[129] It has not been tried in other diseases.
-
Elevation of sRAGE
sRAGE levels can be increased by upregulating the expression of sRAGE and by exogenous
administration. Expression of sRAGE can be upregulated with statins,[130] angiotensin converting enzyme inhibitors,[131] and rosiglitazone.[132] Exogenous administration of sRAGE has been successful in animal model of atherosclerosis.[16]
[17]
[110]
[111] It has not been tried in humans.
-
AGE degrader in vivo
Glyoxalase-1 an endogenous enzymatic degrader of AGE has been described in detail
by Prasad and Bhanumathy.[54] It has not available for use. However, it has been reported that the combined use
of transresveratrol found in grapes and hesperidin found in orange increases the activity
of glyoxalase-1 in placebo-control crossover clinical trial.[133] Considering this, grapes and oranges might be helpful in patients with CAD. AGE
receptor-mediated degrader of AGE (AGE receptor 1 [AGER1]) is not available in the
market. It may serve as a future target for treatment of CAD.
-
Antioxidants
Since ROS is generated with interaction of AGE and RAGE and ROS has been implicated
in the development of atherosclerosis,[120]
[121]
[122] antioxidants may be helpful in AGE-RAGE stress-induced atherosclerosis and CAD.
Antioxidant treatment in AGE–RAGE-induced atherosclerosis has been described in detail
by Prasad and Bhanumathy.[54]
Perspectives
CAD is due to coronary artery atherosclerosis and atherosclerotic plaque rupture resulting
in coronary occlusion. AGE–RAGE axis plays a role in the development of atherosclerosis
in numerous ways including reduction in the levels of NO that is known to protect
atherosclerosis through vasodilation, and inhibits inflammatory mediators, platelet
aggregation, and platelet activation,[134]
[135] enhancement of atherogenic activity of LDL,[26] decreasing the reverse cholesterol transport,[136] and production of ROS, NF-kB, cytokines, adhesion molecules, MCP-1, GM-CSF, and
growth factors described in detail in the earlier section of this chapter.
AGE, RAGE, and sRAGE may play a role in the development of atherosclerosis[9]
[54] and plaque rupture[55]
[56]
[58]
[59]
[60]
[61]
[62]
[63]
[64] AGE levels in serum[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76] and skin autofluorescence[77]
[78]
[79]
[80] in patients with CAD and expression of RAGE[15]
[108]
[109]
[110]
[111]
[112]
[113] in animal model of atherosclerosis are elevated, while serum esRAGE levels are reduced
in patients with CAD. The serum levels of sRAGE in CAD patients are contradictory.
The levels of sRAGE in patients with CAD have been reported to be reduced[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91] in some and elevated[92]
[93]
[94]
[95]
[96] in others. The elevation of sRAGE could be due to patient selection. It is known
that serum sRAGE are elevated in patients with diabetes 1[136] and diabetes 2,[137] and in patients with impaired renal disease especially with end-stage renal disease.[138]
[139]
sRAGE is antiatherogenic because it competes with RAGE for binding with AGE. It is
known that atherosclerosis develops in diabetic patients in spite of high levels of
sRAGE.[23]
[140] One would have expected that high levels of sRAGE would have protected the development
of atherosclerosis in diabetic patients but it did not do so. The reason could be
that elevation of AGE levels is greater than the elevation of sRAGE in diabetic patients.
Hence, measurement of AGE and sRAGE in the same patient would be useful. This will
allow to assess the AGE–RAGE stress that is ratio of AGE/sRAGE.[25] AGE–RAGE stress is a risk factor for disease and high AGE–RAGE stress indicates
the presence and severity of the disease. AGE–RAGE axis comprises of four measurable
components, AGE, RAGE, sRAGE, and esRAGE. Hence, measurement of only one of these
parameters would not give a true biomarker/risk marker. RAGE measurement requires
tissue that is not practical in patients. Simultaneous measurements of AGE and sRAGE
should be performed to assess the AGE–RAGE stress (AGE/sRAGE). Very few investigations
have been performed using AGE–RAGE stress to determine biomarker/risk marker for CAD.[13]
[14]
[114]
[115] It has been reported that AGE/sRAGE are elevated in patients irrespective of low
serum sRAGE in NSTEMI,[13] thoracic aortic aneurysm,[99] hyperthyroidism,[141] hypercholesterolemic patients,[114] and high serum levels of sRAGE in end-stage renal disease.[139] It is stressed that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as biomarker/risk
marker. AGE–RAGE stress is the best biomarker/risk marker of CAD.
Considering involvement of AGE–RAGE axis in the development of CAD some of the therapeutic
interventions, such as reduction in AGE levels and prevention of AGE formation are
easy to follow. Suppression of RAGE expression and elevation of sRAGE needs drugs
that are being used for lowering cholesterol levels, antidiabetic agents, angiotensin
converting enzyme inhibitor, and calcium channel blocker. Patients with CAD are usually
are on one or more of these drugs and hence get benefit. Some the drugs such as AGE
degraders, sRAGE, and RAGE blocker (Azeliragon) are not available in the market for
use in diseases except Alzheimer's disease.
Conclusions
CAD is caused by atherosclerosis of coronary artery and rupture of atherosclerotic
plaques. AGE–RAGE stress can induce atherosclerosis through generation of numerous
atherogenic factors. Serum AGE in CAD patients, expression of RAGE in atherosclerotic
lesion in animals, and AGE–RAGE stress in CAD patients are elevated but serum esRAGE
levels are reduced in CAD patients. sRAGE levels are elevated in some while reduced
in other CAD patients. Treatment of AGE–RAGE stress-induced atherosclerosis includes
reduction in AGE intake, prevention of AGE formation, degradation of AGE in vivo,
suppression of RAGE expression, blockade of AGE–RAGE binding, elevation of sRAGE,
and use of antioxidants. Treatment modalities could prevent, regress, and slow the
progression of CAD.
