http://www.elsevier.com/locate/bba
Biochimica et Biophysica Ac
Review
Bridging advanced glycation end product, receptor for advanced glycation
end product and nitric oxide with hormonal replacement/estrogen therapy
in healthy versus diabetic postmenopausal women: A perspective
Srirupa Mukhopadhyay, Tapan K. Mukherjee*
Pulmonary Division, Department of Internal Medicine, University of Utah Health Science Center, Rm 725 Wintrobe Building,
26 North 1900 East, Salt Lake City, UT 84132-4701, USA
Received 8 February 2005; received in revised form 20 March 2005; accepted 22 March 2005
Available online 8 April 2005
Abstract
Cardiovascular diseases (CVD) are the most significant cause of death in postmenopausal women. The loss of estrogen biosynthesis with
advanced age is suggested as one of the major causes of higher CVD in postmenopausal women. While some studies show beneficial effects
of estrogen therapy (ET)/hormonal replacement therapy (HRT) in the cardiovascular system of healthy postmenopausal women, similar
studies in diabetic counterparts contradict these findings. In particular, ET/HRT in diabetic postmenopausal women results in a seemingly
detrimental effect on the cardiovascular system. In this review, the comparative role of estrogens is discussed in the context of CVD in both
healthy and diabetic postmenopausal women in regard to the synthesis or expression of proinflammatory molecules like advanced glycation
end products (AGEs), receptor for advanced glycation end products (RAGEs), inducible nitric oxide synthases (iNOS) and the anti-
inflammatory endothelial nitric oxide synthases (eNOS). The interaction of AGE–RAGE signaling with molecular nitric oxide (NO) may
determine the level of reactive oxygen species (ROS) and influence the overall redox status of the vascular microenvironment that may
further determine the ultimate outcome of the effects of estrogens on the CVD in healthy versus diabetic women.
D 2005 Elsevier B.V. All rights reserved.
Keywords: AGE; RAGE; Estrogen; HRT; ET; Diabetes; NO; ROS; Postmenopausal women
1. Background
It has long been accepted that estrogens confer their
protective activity against cardiovascular diseases (CVD). In
normal healthy premenopausal women, estrogens control the
cellular level of reactive oxygen species (ROS) and nitric
oxide (NO) generation in such a manner that protecting
against cellular inflammation occurs. After menopause,
women are at greater risk of mortality due to the development
of CVD. The gradual systemic loss of estrogens in the blood
stream of postmenopausal women is a significant factor that
may account for the failure to control oxidative stress and
inflammation in the vascular system. To date, many
observations reveal protective effects of HRT/ET in healthy
0167-4889/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbamcr.2005.03.010
* Corresponding author. Tel.: +1 801 581 7806; fax: +1 801 585 3355.
E-mail address: [email protected] (T.K. Mukherjee).
postmenopausal women. However, a number of recent
studies contradict the decades old generalized concept of
estrogens as a cardioprotective molecule. Particularly, the
role of estrogens as a protective agent in cardiovascular
complications of diabetic women has become an area of
immense interest. Of note, in diabetic women, pre- and
postmenopausal estrogens fail to protect against various
cardiovascular problems. Therefore, diabetes likely abro-
gates the protective vascular functions of estrogens. Again,
increased oxidative stress is one of the major hallmarks of
diabetic vasculature. Advanced glycation end products
(AGEs), receptor for advanced glycation end products
(RAGEs) and nitric oxide (NO) are some of the major
determinants of oxidative stress in the diabetic vasculature.
Estrogen therapy in women may influence the development
of vascular dysfunction at multiple levels including the
bioavailability of NO, expression of RAGE and generation of
ta 1745 (2005) 145 – 155
S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145–155146
reactive oxygen species (ROS). It is therefore important to
examine the modulatory role of estrogens on the expression
of AGE, RAGE, NO and the overall implications of ETon the
oxidative stress in the cardiovasculature of diabetic subjects.
This review discusses the role of estrogens, AGE, RAGE and
NO in the context of CVD in healthy versus diabetic women.
2. Role of estrogen in the context of cardiovascular
disorders in healthy premenopausal and
postmenopausal women
Unlike their postmenopausal counterparts, healthy pre-
menopausal women are protected from various CVD. The
increased risk in postmenopausal women may be associated
with the loss of estrogen biosynthesis [1,2]. Based on these
observations, a number of clinical and pharmacological
experiments have been conducted that indicate a protective
role of estrogen against CVD. Several lines of evidence
indicate that ET/HRT may be associated with an improved
cardiovascular health profile in healthy postmenopausal
women [3–5]. This cardiovascular benefit by estrogen
treatment is mainly observed in younger postmenopausal
women [6,7], but not in women at increased cardiovascular
risk [8]. In today’s world, millions of women routinely use
synthetic/external estrogen as replacement steroids for the
prevention of postmenopausal symptoms, bone loss and
cardiovascular complications. Therefore, studying the
effects of ET/HRT is of significance in terms of clinical,
pharmacological and physiological understanding.
3. Estrogen and cardiovascular disorders in
premenopausal diabetic women
CVD is the number one killer of women regardless of
race and ethnicity. CVD is also the primary cause of death in
80% of diabetics [9]. Recent studies using healthy young
rabbits show that females have a higher level of NO
generation and endothelium-dependent vasodilatation than
their male counterparts [10,11]. This high level of endothe-
lium-dependent NO generation in females is mediated by
estrogen-dependent stimulation of endothelial nitric oxide
synthases (eNOS) [12]. Healthy premenopausal women
have greater endothelium-dependent vasodilatation than
healthy young men, and diabetic premenopausal women
[13]. The endothelial dysfunction of the diabetic premeno-
pausal women is comparable to that of the diabetic men and
is mainly ascribed to the failure of NO synthesis in the
vasculature of diabetic premenopausal women [13].
The vasodilatory action of estrogens is not only mediated
by NO but also by prostacyclin. As compared to men, high
levels of estrogens in premenopausal women induce a
significantly higher level of prostacyclin, a vasodilator agent
[14,15]. Lack of prostacyclin in postmenopausal women [16],
as well as in diabetic rats induced with streptozotocin [17],
identifies prostacyclin as a major affecter of altered vascular
tone. Both in postmenopausal women and streptozotocin-
induced diabetic rats, estrogen treatment induces the gener-
ation of prostacyclin [17]. However, the exact influence of
estrogens on prostacyclin-dependent vasodilatation in pre- and
postmenopausal diabetic women needs further study.
In addition, plasma and urinary oxidative stress indices
have demonstrated that healthy young men have greater
levels of oxidative stress than healthy premenopausal
women [18]. Greater oxidative stress in healthy men as
compared to healthy women is due to an enhanced
generation of 8-iso-PGF2a, one of the free radical catalyzed
products of arachidonic acid [18]. It should be noted that
diabetic vascular tissues of human subjects generate 8-iso-
PGF2a to a higher degree than that of nondiabetics [19].
Although antioxidant treatment was shown to inhibit the
generation of 8-iso-PGF2a [18], the effect of estrogens on
the generation of 8-iso-PGF2a in healthy versus diabetic
pre- and postmenopausal women is yet to be determined.
4. Paradox of the effect of HRT on the cardiovascular
disorders in postmenopausal diabetic women: clinical
studies
Diabetes is one of the greatest risk factors of CVD in
women [20,21]. The prognosis of clinical CVD in diabetic
women is worse than in nondiabetic women [22–24]. In
diabetic postmenopausal women, HRT is associated with
better glycemic control [25–28]. Studies in genetic mouse
models and human subjects confirm the protective effects of
estrogen against diabetes [29]. In contrast, a number of recent
clinical studies indicate that a transitory elevation of coronary
risk is noticed after the commencement of HRT in post-
menopausal women with established coronary heart disease
[30]. In two recent clinical trials, the Heart and Estrogen/
progestin Replacement Study (HERS) [31] and the Women’s
Health Initiative Study (WHI) [32], HRT was not beneficial
for postmenopausal women. In HERS, a trial conducted in
2763 women with known CVD, 19% had diabetes at
baseline. In WHI, a trial conducted in 16,608 women largely
free of CVD at baseline, 4.4% had diabetes at baseline. In
these studies, estrogen combined with progesterone [31,32]
or estrogen alone was employed as replacement steroids [33].
The results of these studies indicate that there is an increased
risk of either stroke [33] or cardiovascular complications in
the postmenopausal women [31,32,34]. More studies are
necessary to completely understand the effects of ET/HRT in
healthy versus diabetic postmenopausal women.
5. Paradox of the recent in vitro experimental results on
estrogen and cardiovascular disorders
Controversy also exists regarding the results of in vitro
experiments on estrogens and CVD. One observation from
S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145–155 147
our group indicates that estrogens might inhibit atheroscle-
rosis in in vitro tissue culture experiments [12]. However,
recent in vitro results both from our lab (unpublished) and
others [35] show that estrogens might actually potentiate
CVD by inducing the expression of the proinflammatory
molecule, RAGE. RAGE is a cell surface receptor respon-
sible for the progression of inflammation in the advanced
stages of cardiovascular complications in diabetic subjects
[36–42]. These seemingly contrasting but interesting results
led us to review the effect of ET/HRT particularly on the
vascular system of diabetic subjects.
6. Functional abnormalities of vascular system in
diabetes and its relationship with estrogen
CVD, particularly atherosclerosis, is a major cause of
disability and death in patients with diabetes [9]. In diabetic
subjects, pathophysiological abnormalities in endothelial,
smooth muscle and platelet function result in functional
abnormalities of coronary, cerebrovascular and peripheral
arteries. The metabolic abnormalities that characterize
diabetes are hyperglycemia, elevated levels of free fatty
acids and insulin resistance. The vascular dysfunction in
diabetic subjects is associated with the accumulation of
AGEs, increased expression of RAGE, decreased bioavail-
ability of eNOS-derived molecular NO and overall
enhanced oxidative stress of the vascular microenvironment.
These vascular abnormalities contribute to the cellular
events that cause vascular complications and subsequently
increase the risk of the adverse cardiovascular events in
patients with diabetes. Estrogen treatment in women may
influence the development of vascular dysfunction at
multiple levels including the bioavailability of NO [12],
expression of RAGE [35] and the generation of reactive
oxygen species (ROS) [43,44]. Further mechanistic studies
in the area of estrogen-dependent modulation of vascular
dysfunction may provide novel strategies for the reduction
of cardiovascular problems in diabetic women.
7. Advanced glycation end products (AGEs) as a
vascular proinflammatory molecule
Both circulatory and cellular levels of AGEs dramatically
increase in aging and diabetes [45]. In aging and diabetes, the
redox potential of the tissue microenvironment is an
important factor that determines the level of formation of
AGEs. Altered glucose metabolism is another major factor of
the biosynthesis of AGEs. Upon exposure to elevated
glucose, proteins and lipids undergo irreversible nonenzy-
matic modifications resulting in the formation of AGEs [46].
Elevated level of AGEs in blood vessels induce a vicious
cycle of metabolic disturbances within the intracellular and
extracellular milieu through both receptor-independent and
receptor-dependent mechanisms. If left unchecked, these
events lead in time to a broad array of proinflammatory
complications in both macrovessel and microvessel struc-
tures, resulting in progressive damage to the vessel wall.
8. Receptor-independent actions of advanced glycation
end products (AGEs) in vascular dysfunction
Circulatory AGEs have direct influence on the structural
integrity of the vessel wall and underlying basement
membranes by inducing the cross-linking of matrix mole-
cules, such as collagen and disruption of matrix–matrix and
matrix–cell interactions [47,48]. Another action of AGEs in
the vasculature is the quenching of nitric oxide (NO),
thereby adversely affecting vascular endothelium and its
protective functions, particularly vascular relaxation [49].
The impaired ability of diabetic vasculature to respond to
stimuli such as acetylcholine suggests that endothelial
dysfunction may be an important indicator in diffuse
cardiovascular diseases as well as atherosclerosis [50,51].
9. Receptor-dependent action of advanced glycation end
products (AGEs) in vascular dysfunction
AGEs interact with vascular and inflammatory cells
through specific cell surface receptors. The most widely
studied receptor is the receptor for AGE (RAGE) [52,53].
RAGE is a multiligand member of the immunoglobulin
superfamily and is expressed on the surface of a variety of
cell types, including endothelial cells, smooth muscle cells,
lymphocytes, monocytes and neurons [54]. RAGE acts as
one of the progression factors of vascular inflammation [55]
both in animal models [56] and most possibly in human
atherosclerotic plaques [57]. Additionally, administration of
the extracellular ligand binding domain of the receptor
(soluble RAGE) to APO-E-null mice bred into a diabetic
background (db/db) suppressed the accelerated development
and progression of atherosclerosis [58]. These observations
indicate that RAGE acts as a potential proatherogenic
molecule involved in the advanced stages of atherosclerosis
of diabetic subjects.
Recently observations demonstrate that soluble RAGE
(sRAGE) may function as a ‘‘decoy’’ by binding RAGE
ligands and preventing their interaction with cell surface
RAGE. This work further indicated that RAGE�/� mice
displayed normal innate and adaptive immune response as
compared to the wild type mice used as control. Surpris-
ingly, RAGE�/� mice were protected from delayed-type
hypersensitivity (DTH) responses in a model of septic shock
[59]. These results further indicate that the innate immune
response is controlled by RAGE not only at the initiating
steps but also in perpetuation. Since both adaptive and
innate immune responses are capable of initiating inflam-
mation, evaluating the role of RAGE/sRAGE in diabetic
animal models is essential.
S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145–155148
10. AGE–RAGE interaction causes subcellular signaling
leading to the generation of ROS and vascular
dysfunction
A number of studies suggest the mechanism of action of
RAGE in evoking vascular diseases. RAGE interacts with
numerous ligands including AGEs. The interaction of
RAGE with its ligands generates ROS via the activation
of NADPH oxidase and proinflammatory transcription
factor NF-nB that in turn engage in proinflammatory and
prooxidative signaling events in cells [60–63]. NF-nB may
contribute to the development of a proinflammatory and
prooxidative state by stimulating the expression of numer-
ous target genes, such as tissue factor (TF) [64], vascular
cell adhesion molecule-1 (VCAM-1) [65], p21Ras, extrac-
ellular signal-regulated kinase (ERK) 1/2 [62] and RAGE
itself [35]. Activation of these prooxidative genes may
contribute to a vicious proinflammatory cycle at inflamed
foci leading to the progressive damage of the vasculature
(Fig. 1). In addition, recent observation by our group is that
stimulation of endothelial cells by TNFa, a strong proin-
flammatory cytokine, causes a substantial induction of
Fig. 1. Schematic presentation of the effects of AGE–RAGE interaction.
Interaction of circulatory AGE in bloodstream with RAGE at the cell
surface induces the generation of reactive oxygen species (ROS) that in turn
activates transcription factor NF-nB. NF-nB subsequently activates several
proinflammatory genes including tissue factor (TF), ERK 1/2, Ras, vascular
cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1
(ICAM1) and receptor for advanced glycation end products (RAGE)
causing cellular inflammation. j Indicates gene activation.
mitochondrial respiratory chain and endogenous oxidore-
ductases including NADPH oxidase that leads to the
increased generation of ROS (unpublished). This excessive
level of ROS induces RAGE expression via the activation of
NF-B. The precise cellular mechanism through which TNFa
may induce RAGE expression is represented through a
schematic diagram (Fig. 2). In summary, situations may
occur in which increased ROS may induce RAGE expres-
sion that in turn induces further ROS generation [60–63],
thus initiating a self-amplifying cycle.
11. Effect of estrogen as an inducer of AGE–RAGE
signaling
Recent observations implicate the involvement of estro-
gens in AGE–RAGE signaling. One recent observation
demonstrates that estrogens inhibited the synthesis of AGE,
the substrate of RAGE in vaginal epithelial tissues of
postmenopausal women. These findings indicate a potential
anti-inflammatory and protective role for estrogen [66]. In
contrast, another recent observation demonstrates that 10
nM of 17-hE2, an estrogen predominantly found in the
circulation of premenopausal women, might induce the
expression of RAGE in in vitro cultured human endothelial
cells. This supraphysiological concentration of estrogen is
attainable in vivo only during pregnancy, indicating a
possible link between pregnancy related vascular compli-
cations and increased expression of RAGE [35]. In addition,
our recent work reveals that estrogens stimulate RAGE
expression at physiological concentrations in cultured
endothelial cells (unpublished). However, like others, the
optimum level of RAGE expression in our experiments is
detected at 10 nM of 17-hE2.
We also observed that the ERa agonist ethinyl estradiol
(a major component of synthetic contraceptive) is the
strongest activator of estrogen-dependent RAGE expression
and the ERh agonist 17-epiestriol (an estrogen metabolite
present in vivo) only minimally induces RAGE. The precise
cellular mechanism by which estrogens may stimulate
RAGE expression in these endothelial cell culture experi-
ments via ERa is as follows: Stimulation of cells with
estrogensY binding of estrogen to ERaY binding of ERa
to the transcription factor Sp1Y binding of Sp1 to the Sp1
recognition sequence of RAGE promoterY activation of
RAGE promoterY induction of RAGE expression. Of note,
these in vitro observations need to be further evaluated by in
vivo experiments.
12. Possible role of estrogen in RAGE signaling in
homeostasis versus pathophysiological conditions
Based on the results of the in vitro experiments that
estrogens stimulate RAGE expression at physiological
concentrations (unpublished), one possible prediction is that
Fig. 3. Schematic presentation of the possible effects of estrogens on AGE–
RAGE and nitric oxide signaling (NO) in cellular homeostasis. In
homeostasis estrogens activate eNOS and inhibit iNOS that causes basal
level of NO generation leading to anti-inflammatory and cellular protective
actions. Estrogens might decrease AGE level and increases the basal level
of RAGE in cells in homeostatic condition. The high basal level of RAGE
in turn might maintain the homeostasis of cell proliferation, signaling and
cell survival. j Indicates activation and , indicates inhibition, respectively,
? indicates undefined.
Fig. 2. Schematic presentation of the effects of TNFa on RAGE expression.
Stimulation of cells with TNFa induces the generation of reactive oxygen
species (ROS) through the activation of mitochondrial respiratory chain and
NADPH oxidase. ROS in turn activates the proinflammatory transcription
factor NF-nB that further activates RAGE promoter and induces cell
surface RAGE expression. The ROS generation by NADPH oxidase
and mitochondria activates each other by positive feedback. ˝ Indicates
bi-directional activation.
S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145–155 149
estrogens stimulate RAGE expression in vivo. During
homeostasis, most of the tissues express a basal level of
RAGE [54]. This basal level of RAGE expression might be
involved in embryonic growth and development [67], cellular
proliferation and survival [68] and the activation of various
signaling events [69]. Moreover, the basal level of RAGE
expression is comparatively high in pulmonary tissues in
comparison to most other tissues [55]. RAGE expression is
detected at the basolateral membrane of alveolar epithelial
type 1 cells (AT1) and may function to assist cellular
adherence and spreading. RAGE-induced spreading of AT1
cells is significant in that it may promote morphological
changes essential for proper gas exchange. The high level of
RAGE in pulmonary tissues sharply declines in specific
pathophysiological conditions, such as non-small cell lung
carcinoma [70]. Based on this observation, one recent study
speculated that high basal level expression of RAGE actually
protects lung tissues from becoming a carcinoma [70].
Therefore, it is possible that by stimulating the basal level
expression of RAGE at physiological concentration, estrogen
may help to maintain the homeostasis of RAGE-dependent
signaling events (Fig. 3). However, RAGE null mice have no
apparent phenotype with respect to growth and development
or reproduction [59]. Therefore, this subject remains open for
further investigation.
In pathophysiological conditions there is elevated
expression of RAGE possibly due to enhanced proinflam-
mation and prooxidation. Administration of synthetic estro-
gens to postmenopausal women might further exacerbate
the level of proinflammation and prooxidation that lead to
the progression of various cardiovascular complications by
enhancing the expression of RAGE (Fig. 4). Thus, based on
an overall interpretation, one possibility that the mechanism
of estrogen-dependent RAGE signaling may differ in
homeostasis and pathophysiological conditions. However,
this needs to be further addressed in suitably designed future
experiments.
13. Bridging of NO and ROS as effector molecules with
AGE–RAGE signaling in diabetes
Oxidative stress is one of the major detrimental factors of
diabetic vascular dysfunction [71]. Allopurinol, a potent
xanthine oxidase inhibitor [72], angiotensin-converting
enzyme inhibitors [73] and antioxidant treatment [74] all
normalize endothelial dysfunction in diabetes, indicating the
existence of oxidative stress in diabetic vasculature. A
number of recent studies indicate that increased synthesis
of AGEs lead to excessive generation of ROS [36,60–63].
Excess ROS overwhelms cellular antioxidant defense mech-
anisms [75] and react with molecular nitric oxide to generate
Fig. 4. Schematic presentation of the possible effects of estrogen on AGE–
RAGE and nitric oxide signaling (NO) in diabetes. Diabetic vascular tissues
are characterized by high level of both NO and ROS generation. In
diabetes, estrogen might inhibit eNOS and activate iNOS that causes high
level of NO generation in the cell. Estrogens might increase the AGE–
RAGE level and activate AGE–RAGE interaction causing a high level of
ROS generation in diabetic condition. High level of NO and ROS together
causes proinflammation, cellular toxicity and damage. j Indicates activationand , indicates inhibition, respectively, ? indicates undefined.
S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145–155150
highly toxic and deleterious peroxinitrite [76], which can
cause profound vascular damage [74,76]. Therefore, AGE–
RAGE signaling may correlate with the redox status of cells
via both ROS and NO.
Substantial evidence indicates that diabetic vascular
dysfunction is associated with marked alteration of NO
synthesis both in animal models and in human subjects
[49,77–80]. For example, treatment with streptozotocin to
create diabetes in animals impairs the vascular NO signaling
pathway that leads to vascular dysfunction [81]. In human
subjects, NO bioavailability is diminished early in the
course of diabetes, as demonstrated in subjects with the
metabolic syndrome [82,83]. Under diabetic conditions,
endothelial cells also fail to protect themselves from
oxidative stress apparently due to decreased bioavailability
of eNOS derived NO [74]. In contrast, diabetic subjects
have a sustained high level of iNOS-induced NO that can be
toxic due to the generation of peroxinitrite via a reaction
with superoxide radicals. This mechanism therefore may
play a central role in the pathophysiology of inflammation
and oxidative stress [74,76]. Accordingly, functional
expression of iNOS has been reported in smooth muscle
cells (SMCs) from the superior mesenteric arteries of rats
with chronic diabetes [81]. Thus, the iNOS-mediated
increase in NO formation may be one of the major
proinflammatory mediators in diabetic vascular dysfunction.
Since estrogens are important anti-inflammatory modulators
of NO synthesis in females, it is therefore essential to
reexamine estrogen-dependent NO signaling mechanisms in
postmenopausal diabetic women.
14. Effects of estrogen on nitric oxide signaling in
healthy versus diabetic subjects
A number of recent in vivo and in vitro observations
including our own [12,84] show that estrogens can induce the
expression of eNOS both in animal models and in cultured
human endothelial cells. Induction of eNOS-dependent NO
production may be one of the protective mechanisms through
which estrogen may attenuate atherosclerosis. Some of the
beneficial effects of eNOS-derived NO are vasodilation,
inhibition of adhesion molecule expression and inhibition of
monocyte migration [84], which all contribute to the
attenuation of inflammation (Fig. 3). Estrogens also inhibit
IL-1beta induced iNOS expression in rat aortic endothelial
cells indicating a potential protective role [85]. Moreover,
recent studies indicate that transdermal administration of
either conjugated estrogens combined with continuous
progestin or estrogen alone in postmenopausal women for
successive 12 months increase serum NO level [86]. There-
fore, estrogens function via NO pathway to protect against
cellular inflammation.
Diabetic vascular tissues behave differently in response
to estrogens (Fig. 4). For example, the lack of protective
effects of estrogen in diabetes may be ascribed to the failure
of estrogen to reverse the impaired basal release of NO and
abnormal relaxation to histamine that are observed in the
aorta of diabetic rats [87]. Diabetes also undermines the
protective effect by inducing iNOS expression in rat aortic
smooth muscle cells through overexpression of estrogen
receptor-beta (ERh) [88]. It is therefore possible that
diabetic vascular tissues may loose many of the protective
effects of estrogens. A comparative study of NO and AGE–
RAGE signaling pathways of healthy versus diabetic
postmenopausal women during ET/HRT may lead to a
better understanding of the usefulness of ET in the
vasculature and its overall implication during diabetes.
15. The influence of overall oxidative stress on the
vascular system of diabetic subjects
Based on the above scenarios of AGE–RAGE interaction
and estrogen–RAGE/estrogen–NO signaling in diabetic
vasculature, it can be speculated that an overall state of
oxidative stress is at least partially responsible for the
vascular complications in diabetes [71–89]. During diabetic
conditions, excessive formation of ROS overcomes cellular
S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145–155 151
antioxidant defense mechanisms, resulting in ROS-initiated
modifications of lipids, proteins, carbohydrates and DNA
[75]. The increased generation of ROS in diabetes is
associated with high levels of d-glucose, AGEs and glycated
lipo-proteins. These altered carbohydrate and protein mole-
cules in turn further induce the generation of ROS through the
activation of themitochondrial respiratory chain andNADPH
oxidases [80,90]. In the presence of high blood glucose levels
in diabetes, the increased vascular generation of ROS plays
an intermediate role in the pathogenesis of macro as well as
microangiopathic complications by quenching the protective
bioactivity of NO [49]. Given this scenario, intervention
targeting of signaling pathways involved in the generation of
ROS may prove highly beneficial in the prevention of long-
term diabetic complications.
16. Role of estrogen in controlling the overall oxidative
stress of diabetic vasculature
Oxidative stress plays a very important role in diabetic
vascular and neuronal disease [90]. Although general
consensus is yet to be achieved, it is assumed that some
of the vasculoprotective actions of estrogens are due to their
antioxidative and anti-inflammatory functions [91–95]. The
antioxidative action of estrogens is reflected in estrogen-
dependent protection against neurological disorders [91–
93] and inhibition of smooth muscle cell proliferation
[94,95]. Of note, inhibition of smooth muscle cell prolifer-
ation is an antiatherosclerotic function associated with
estrogens. However, while one recent study indicated that
estrogens restore cellular proliferation in dentate gyrus and
subventicular zone of the nervous system in streptozotocin
induced diabetic rats [96], other studies suggested that the
neuroprotective benefits of HRT might be lost in the
diabetic female rats [97].
In tissue culture experiments, while estrogen inhibited
ROS generation in cultured human endothelial cells [44]
and bovine aortic endothelial cells [98], estrogen also
induced ROS generation in the uterine tissues of primate
mammals and HepG2 cells [99–103].
The exact influence of estrogens on the modulation of
oxidative stress in the cardiovasculature of postmenopausal
women remains controversial. One study indicated that HRT
attenuates oxidative stress in women undergoing natural or
surgical menopause [104]. Besides HRT, antioxidant vita-
mins are widely used for the secondary prevention of
coronary artery diseases in postmenopausal women. A
combination of HRT and antioxidant vitamins reduced the
oxidative stress of both diabetic and nondiabetic postme-
nopausal women [105]. However, a number of other studies
attributed no beneficial effects of HRT on the oxidative
stress in postmenopausal women [106]. Further studies in
the postmenopausal women with established CAD showed
that neither antioxidant vitamins nor HRT provide benefit.
Instead, a potential for harm is suggested with each
treatment [107]. The exact reason for the failure of HRT
or antioxidant vitamin treatment to protect the cardiovascu-
lature of postmenopausal women with established coronary
artery disease is yet to be determined.
17. Conclusion
Although general consensus is yet to be achieved, it
seems that the diabetic vasculature of postmenopausal
women may loose many inherent protective properties
mediated by estrogens. Besides individual variation and
the severity of diabetic vascular complications, the failure of
ET/HRT to improve the cardiovascular complications in
diabetic subjects depends upon a number of determining
factors, i.e., decreased level of estrogen with advanced age,
family history of diabetes, prior exposure to hyperglycemia
during pregnancy and type of administered synthetic estro-
gen. Other possible factors include the duration of estrogen
treatment and possible recent myocardial infarctions (MI)
[108,109]. Recent studies also indicate that the genetic
variations of estrogen receptors are an important determi-
nant of cardiovascular complications [110–112]. In addi-
tion, cyclic alterations of the dose of administered estrogen
might prove beneficial to the postmenopausal women since
cyclic variation of the level of estrogen hormone is a normal
physiological phenomenon in menstruating women. Alter-
ations of one or more of the above factors might influence
the overall vascular system of diabetic women to function
differently in response to ET/HRT as compared to the
normal vasculature of nondiabetic healthy postmenopausal
women. Because of these potential effects, a large number
of scientists believe that ET/HRT may improve the
prognosis of postmenopausal women with vascular compli-
cations [113]. In addition to considering all of the above
factors, measurement of the cellular/circulatory level of
AGE, RAGE, iNOS, eNOS and checking the overall
oxidative status of the vascular system of postmenopausal
women during ET/HRT may be crucial in clarifying specific
benefits of ET/HRT.
Acknowledgement
National Institute of Health Grant HL67281 supported
this work.
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