Bridging advanced glycation end product, receptor for advanced glycation

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.


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.


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.


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


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.

References

[1] T. Gordon, W.B. Kannel, M.C. Hjortland, P.M. McNamara, Meno-

pause and coronary heart disease. The Framingham Study, Ann.

Intern. Med. 89 (1978) 157–161.

[2] T.L. Bush, Preserving cardiovascular benefits of hormone

replacement therapy, J. Reprod. Med. 45 (2000) 259–273.

[3] A. Gottsater, M. Rendell, U.L. Hulthen, E. Berntorp, I. Mattiasson,

Hormone replacement therapy in healthy postmenopausal women: a


randomized, placebo-controlled study of effects on coagulation and

fibrinolytic factors, J. Intern. Med. 249 (2001) 237–246.

[4] C. Varas-Lorenzo, L.A. Garcia-Rodriguez, S. Perez-Gutthann, A.

Duque-Oliart, Hormone replacement therapy and incidence of acute

myocardial infarction: a population-based nested case-control study,

Circulation 101 (2000) 2572–2578.

[5] L. Mosca, The role of hormone replacement therapy in the prevention

of postmenopausal heart disease, Arch. Intern. Med. 160 (2000)

2263–2272.

[6] C.D. Furberg, B.M. Psaty, Review: hormone replacement therapy

may reduce the risk for death in younger but not older postmeno-

pausal women, ACP J. Club 142 (2005) 1.

[7] M.J. Stampfer, G.A. Colditz, Estrogen replacement therapy and

coronary heart disease: a quantitative assessment of the epidemio-

logic evidence, Prev. Med. 20 (1991) 47–63.

[8] P. Angerer, S. Stork, W. Kothny, P. Schmitt, C. von Schacky, Effect

of oral postmenopausal hormone replacement on progression of

atherosclerosis: a randomized, controlled trial, Arterioscler. Thromb.

Vasc. Biol. 21 (2001) 262–268.

[9] J. Waltenberger, Impaired collateral vessel development in diabetes:

potential cellular mechanism and therapeutic implications, Cardio-

vasc. Res. 49 (2001) 554–560.

[10] T. Hayashi, J.M. Fukuto, L.J. Ignarro, G. Chaudhuri, Gender

differences in atherosclerosis: possible role of nitric oxide,

J. Cardiovasc. Pharmacol. 26 (1995) 792–802.

[11] T. Hayashi, J.M. Fukuto, L.J. Ignarro, G. Chaudhuri, Basal release of

nitric oxide from aortic rings is greater in female rabbits than in

male rabbits: implications for atherosclerosis, Proc. Natl. Acad. Sci.

U. S. A. 89 (1992) 11259–11263.

[12] T.K. Mukherjee, L. Nathan, H. Dinh, S.T. Reddy, G. Chaudhuri,

17-epiestriol, an estrogen metabolite, is more potent than estradiol

in inhibiting vascular cell adhesion molecule 1 (VCAM1) mRNA

expression, J. Biol. Chem. 278 (2003) 11746–11752.

[13] H.O. Steinberg, G. Paradisi, J. Cronin, K. Crowde, A. Hempfling, G.

Hook, A.D. Baron, Type II diabetes abrogates sex differences in

endothelial function in premenopausal women, Circulation 101

(2000) 2040–2046.

[14] J.M. Orshal, R.A. Khalil, Gender, sex hormones and vascular tone,

Am. J. Physiol., Comp. Physiol. 286 (2004) R233–R249.

[15] J. Thompson, R.A. Khalil, Gender differences in the regulation of

vascular tone, Clin. Exp. Pharmacol. Physiol. 30 (2003) 1–15.

[16] A. Steinleitner, F.Z. Stanczyk, J.H. Levin, G. d’Ablaing III, M.A.

Vijo, V.L. Shahbazzian, R.A. Lobo, Decreased in vitro production of

6-keto-prostaglandin F1 alpha by uterine arteries from postmeno-

pausal women, Am. J. Obstet. Gynecol. 161 (1989) 1677–1681.

[17] A. Cignarella, C. Bolego, C. Pinna, R. Zanardo, I. Eberini, L. Puglisi,

The influence of sex hormones on vascular responses in the aorta of

streptozotocin-diabetic male rats, Naunyn-Schmiedeberg’s Arch.

Pharmacol. 361 (2000) 514–520.

[18] T. Ide, H. Tsutsui, N. Ohashi, S. Hayashidani, N. Suematsu, M.

Tsuchiashi, H. Tamai, A. Takeshita, Greater oxidative stress in

healthy young men compared with premenopausal women,

Arterioscler., Thromb., Vasc. Biol. 22 (2002) 438–442.

[19] G. Davi, P. Alessandrini, A. Mezzetti, G. Minotti, T. Bucciarelli, F.

Costantini, F. Cipollone, G.B. Bon, G. Ciabattoni, C. Patrono, In

vivo formation of 8-Epi-prostaglandin F2 alpha is increased in

hypercholesterolemia, Arteoscler., Thromb., Vasc. Biol. 17 (1997)

3230–3235.

[20] V. Brezinka, I. Padmos, Coronary heart disease risk factors in

women, Eur. Heart J. 15 (1994) 1571–1584.

[21] K. Bibbins-Domingo, F. Lin, E. Vittinghoff, E. Barrett-Connor, S.B.

Hulley, D. Grady, M.G. Shlipak, Predictors of heart failure among

women with coronary disease, Circulation 110 (2004) 1424–1430.

[22] P.H. Stone, J.E. Muller, T. Hartwell, B.J. York, J.D. Rutherford,

C.B. Parker, Z.G. Turi, H.W. Strauss, J.T. Willerson, T. Robertson,

et al.The MILIS Study Group, The effect of diabetes mellitus on

prognosis and serial left ventricular function after acute myocardial

infarction: contribution of both coronary disease and diastolic left

ventricular dysfunction to the adverse prognosis, J. Am. Coll.

Cardiol. 14 (1989) 49–57.

[23] D.E. Singer, A.W. Moulton, D.M. Nathan, Diabetic myocardial

infarction: interaction of diabetes with other preinfarction risk

factors, Diabetes 38 (1989) 350–357.

[24] J.W. Smith, F.I. Marcus, R. Serokman, Prognosis of patients with

diabetes mellitus after acute myocardial infarction, Am. J. Cardiol. 54

(1984) 718–721.

[25] A. Ferrara, A.J. Karter, L.M. Ackerson, J.Y. Liu, J.V. Selby,

Hormone replacement therapy is associated with better glycemic

control in women with type 2 diabetes, the Northern California

Kaiser Permanente Diabetes Registry, Diabetes Care 24 (2001)

1144–1150.

[26] W. Cefalu, The use of hormone replacement therapy in postmeno-

pausal women with type 2 diabetes, J. Women’s Health Gend. Based

Med. 10 (2001) 241–255.

[27] S.L. Palin, S. Kumar, D.W. Sturdee, A.H. Barnett, HRT in

women with diabetes—Review of the effects on glucose and lipid

metabolism, Diabetes Res. Clin. Prac. 54 (2001) 67–77.

[28] K.E. Friday, C. Dong, R.U. Fontenot, Conjugated equine estrogen

improves glycemic control and blood lipoproteins in postmenopausal

women with type 2 diabetes, J. Clin. Endocrinol. Metab. 86 (2001)

48–52.

[29] J.F. Louet, C. LeMay, F. Mauvais-Jarvis, Antidiabetic actions of

estrogen: insight from human and genetic mouse models, Curr.

Athreoscler. Rep. 6 (2004) 180–185.

[30] S.R. Heckbert, R.C. Kaplan, N.S. Weiss, B.M. Psaty, D. Lin,

C.D. Furberg, J.R. Starr, G.D. Anderson, A.Z. LaCroix, Risk of

recurrent coronary events in relation to use and recent initiation

of postmenopausal hormone therapy, Arch. Intern. Med. 161

(2001) 1709–1713.

[31] S. Hulley, D. Grady, T. Bush, C. Furberg, D. Herrington, B. Riggs, E.

Vittinghoff, Randomized trial of estrogen plus progestin for

secondary prevention of coronary heart disease in postmenopausal

women: Heart and Estrogen/Progestin Replacement Study (HERS)

Research Group, JAMA 280 (1998) 605–613.

[32] J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, C.

Kooperberg, M.L. Stefanick, R.D. Jackson, S.A. Beresford, B.V.

Howard, K.C. Johnson, J.M. Kotchen, J. Ockene, Writing Group for

the Women’s Health Initiative Investigators, Risks and benefits of

estrogen plus progestin in healthy postmenopausal women: principal

results from the Women’s Health Initiative randomized controlled

trial, JAMA 288 (2002) 321–333.

[33] S.B. Hulley, D. Grady, The WHI estrogen-alone trial—Do things

look any better? JAMA 291 (2004) 1769–1771.

[34] C.D. Furberg, E. Vittinghoff, M. Davidson, D.M. Herrington, J.A.

Simon, N.K. Wenger, S. Hulley, Subgroup interactions in the

heart and estrogen/progestin replacement study: lessons learned,

Circulation 105 (2002) 917–922.

[35] N. Tanaka, H. Yonekura, S. Yamagishi, H. Fujimori, Y. Yamamoto,

H. Yamamoto, The receptor for advanced glycosylation end products

is induced by the glycation product themselves and TNF-alpha

through nuclear factor kappa B and by 17-beta-estradiol through Sp1

in human vascular endothelial cells, J. Biol. Chem. 275 (2000)

25781–25790.

[36] A.M. Schmidt, O. Hori, J. Brett, S.D. Yan, J.L. Wautier, D. Stern,

Cellular receptors for advanced glycation end products: implications

for induction of oxidant stress and cellular dysfunction in the

pathogenesis of vascular lesions, Arterioscler. Thromb. 14 (1994)

1521–1528.

[37] A.M. Schmidt, S.D. Yan, J.L. Wautier, D. Stern, Activation of

receptor for advanced glycation end products: a mechanism for

chronic vascular dysfunction in diabetic vasculopathy and athero-

sclerosis, Circ. Res. 84 (1999) 489–497.

[38] J.M. Forbes, L.T. Yee, V. Thallas, M. Lassila, R. Candido, K.A.

Jandeleit-Dahm, M.C. Thomas, W.C. Burns, E.K. Deemer, S.M.


Thorpe, M.E. Cooper, T.J. Allen, Advanced glycation end product

interventions reduce diabetes-accelerated atherosclerosis, Diabetes

53 (2004) 1813–1823.

[39] L.G. Bucciarelli, T. Wendt, W. Qu, Y. Lu, E. Lalla, L.L. Rong, M.T.

Goova, B. Moser, T. Kislinger, D.C. Lee, Y. Kashyap, D.M. Stern,

A.M. Schmidt, RAGE blockade stabilizes established atherosclerosis

in diabetic apolipoprotein E-null mice, Circulation 106 (2002)

2827–2835.

[40] L. Park, K.G. Raman, K.J. Lee, Y. Lu, L.J. Ferran Jr., W.S. Chow, D.

Stern, A.M. Schmidt, Suppression of accelerated diabetic athero-

sclerosis by the soluble receptor for advanced glycation endproducts,

Nat. Med. 4 (1998) 1025–1031.

[41] Y. Chen, S.S. Yan, J. Colgan, H.P. Zhang, J. Luban, A.M. Schmidt,

D. Stern, K.C. Herold, Blockade of late stages of autoimmune

diabetes by inhibition of the receptor for advanced glycation end

products, J. Immunol. 173 (2004) 1399–1405.

[42] Y. Yamamoto, S. Yamagishi, H. Yonekura, T. Doi, H. Tsuji, I. Kato,

S. Takasawa, H. Okamoto, J. Abedin, N. Tanaka, S. Sakurai, H.

Migita, H. Unoki, H. Wang, T. Zenda, P.S. Wu, Y. Segawa, T.

Higashide, K. Kawasaki, H. Yamamoto, Roles of the AGE–RAGE

system in vascular injury in diabetes, Ann. N. Y. Acad. Sci. 902

(2000) 163–170.

[43] J. Chen, Y. Li, J.A. Lavigne, M.A. Trush, J.D. Yager, Increased

mitochondrial superoxide production in rat liver mitochondria, rat

hepatocytes and HepG2 cells following ethinyl estradiol treatment,

Toxicol. Sci. 51 (1999) 224–235.

[44] A.H. Wagner, M.R. Schroeter, M. Hecker, 17-beta-estradiol

inhibition of NADPH oxidase expression in human endothelial

cells, FASEB J. 15 (2001) 2121–2130.

[45] M. Brownlee, Advanced protein glycosylation in diabetes and aging,

Annu. Rev. Med. 46 (1995) 223–234.

[46] A.M. Schmidt, S.D. Yan, D.M. Stern, The dark side of glucose, Nat.

Med. 1 (1995) 1002–1004.

[47] S. Tanaka, G. Avigad, B. Brodsky, E.F. Eikenberry, Glycation

induces expansion of the molecular packing of collagen, J. Mol.

Biol. 203 (1988) 495–505.

[48] C.S. Haitoglou, E.C. Tsilibary, M. Brownlee, A.S. Charonis, Altered

cellular interactions between endothelial cells and nonenzymatically

glycosylated laminin/type IV collagen, J. Biol. Chem. 267 (1992)

12404–12407.

[49] R. Bucala, K.J. Tracey, A. Cerami, AGEs quench nitric oxide and

mediate defective endothelium-dependent vasodilatation in exper-

imental diabetes, J. Clin. Invest. 87 (1991) 432–438.

[50] A.S. De Vriese, T.J. Verbeuren, J. Van de Voorde, N.H. Lameire,

P.M. Vanhoutte, Endothelial dysfunction in diabetes, Br. J.

Pharmacol. 130 (2000) 963–974.

[51] A.E. Caballero, S. Arora, R. Saouaf, S.C. Lim, P. Smakowski, J.Y.

Park, G.L. King, F.W. LoGerfo, E.S. Horton, A. Veves, Micro-

vascular and macrovascular reactivity is reduced in subjects at risk

for type 2 diabetes, Diabetes 48 (1999) 1856–1862.

[52] A.M. Schmidt, O. Hori, R. Cao, S.D. Yan, J. Brett, J.L. Wautier, S.

Ogawa, K. Kuwabara, M. Matsumoto, D. Stern, RAGE: a novel

cellular receptor for advanced glycation end products, Diabetes 45

(1996) S77–S80.

[53] P.J. Thornalley, Cell activation by glycated proteins. AGE receptors,

receptor recognition factors and functional classification of AGEs,

Cell. Mol. Biol. 44 (1998) 1013–1023.

[54] J. Brett, A.M. Schmidt, S.D. Yan, Y.S. Zou, E. Weidman, D. Pinsky,

R. Nowygrod, M. Neeper, C. Przysiecki, A. Shaw, Survey of the

distribution of a newly characterized receptor for advanced glycation

end products in tissues, Am. J. Pathol. 143 (1993) 1699–1712.

[55] A.M. Schmidt, S.D. Yan, S.F. Yan, D.M. Stern, The multiligand

receptor RAGE as a progression factor amplifying immune and

inflammatory responses, J. Clin. Invest. 108 (2001) 949–955.

[56] T. Sakaguchi, S.F. Yan, S.D. Yan, D. Belov, L.L. Rong, M. Sousa, M.

Andrassy, S.P. Marso, S. Duda, B. Arnold, B. Liliensiek, P.P.

Nawroth, D.M. Stern, A.M. Schmidt, Y. NAKA, Central role of

RAGE dependent neointimal expansion in arterial restenosis, J. Clin.

Invest. 111 (2003) 959–972.

[57] F. Cipollone, A. Iezzi, M. Fazia, M. Zucchelli, B. Pini, C. Cuccurullo,

D. De Cesare, G. De Blasis, R. Muraro, R. Bei, F. Chiarelli, A.M.

Schmidt, F. Cuccurullo, A. Mezzetti, The receptor RAGE as

progression factor amplifying arachidonate dependent inflammatory

and proteolytic response in human atherosclerotic plaques, role of

glycemic control, Circulation 108 (2003) 1070–1077.

[58] Z. Zhou, K. Wang, M.S. Penn, S.P. Marso, M.A. Lauer, F. Forudi, X.

Zhou, W. Qu, Y. Lu, D.M. Stern, A.M. Schmidt, A.M. Lincoff, E.J.

Topol, Receptor for AGE (RAGE) mediates neointimal formation in

response to arterial injury, Circulation 107 (2003) 2238–2243.

[59] B. Liliensiek, M.A. Weigand, A. Bierhaus, W. Nicklas, M. Kasper, S.

Hofer, J. Plachky, H.J. Grone, F.C. Kurschus, A.M. Schmidt, S.D.

Yan, E. Martin, E. Schleiicher, D.M. Stern, G.G. Hammerling, P.P.

Nawroth, B. Arnold, Receptor for advanced glycation end products

(RAGE) regulates sepsis but not the adaptive immune response,

J. Clin. Invest. 113 (2004) 1641–1650.

[60] S.D. Yan, A.M. Schmidt, G.M. Anderson, J. Zhang, J. Brett, Y.S.

Zou, D. Pinsky, D. Stern, Enhanced cellular oxidant stress by the

interaction of advanced glycation end products with their receptors/

binding proteins, J. Biol. Chem. 269 (1994) 9889–9897.

[61] M.P. Wautier, O. Chappey, S. Corda, D.M. Stern, A.M. Schmidt, J.L.

Wautier, Activation of NADPH oxidase by AGE links oxidative

stress to altered gene expression via RAGE, Am. J. Physiol:

Endocrinol. Metab. 280 (2001) E685–E694.

[62] H.M. Lander, J.M. Tauras, J.S. Ogiste, O. Hori, R.A. Moss, A.M.

Schmidt, Activation of the receptor for advanced glycation end

products triggers a p21 (ras)-dependent mitogen-activated protein

kinase pathway regulated by oxidant stress, J. Biol. Chem. 272

(1997) 17810–17814.

[63] J.L. Wautier, M.P. Wautier, A.M. Schmidt, G.M. Anderson, O. Hori,

C. Zoukourian, L. Capron, O. Chappey, S.D. Yan, J. Brett,

Advanced glycation end products (AGEs) on the surface of diabetes

erythrocytes bind to the vessel wall via a specific receptor inducing

oxidant stress in vasculature: a link between surface associated

AGEs and diabetic complications, Proc. Natl. Acad. Sci. U. S. A. 91

(1994) 7742–7746.

[64] A. Bierhaus, T. Illmer, M. Kasper, T. Luther, P. Quehenberger, H.

Tritschler, P. Wahl, R. Ziegler, M. Muller, P.P. Nawroth, Advanced

glycation end product (AGE)-mediated induction of tissue factor in

cultured endothelial cells is dependent on RAGE, Circulation 96

(1997) 2262–2271.

[65] A.M. Schmidt, O. Hori, J.X. Chen, J.F. Li, J. Crandall, J. Zhang, R.

Cao, S.D. Yan, J. Brett, D. Stern, Advanced glycation endproducts

interacting with their endothelial receptor induce expression of vas-

cular cell adhesion molecule-1 (VCAM-1) in cultured human endo-

thelial cells and in mice: a potential mechanism for the accelerated

vasculopathy of diabetes, J. Clin. Invest. 96 (1995) 1395–1403.

[66] S. Jackson, M. James, P. Abrams, The effect of estradiol on vaginal

collagen metabolism in postmenopausal women with genuine stress

incontinence, BJOG 109 (2002) 344–399.

[67] O. Hori, J. Brett, T. Slattery, R. Cao, J. Zhang, J.X. Chen, M.

Nagashima, E.R. Lundh, S. Vijay, D. Nitecki, The receptor for

advanced glycation end product (RAGE) is a cellular binding site for

amphoterin: mediation of neurite outgrowth and co-expression of

RAGE and amphoterin in the developing nervous system, J. Biol.

Chem. 270 (1995) 25752–25761.

[68] T. Arumugam, D.M. Simeone, A.M. Schmidt, C.D. Logsdon,

S100P stimulates cell proliferation and survival via receptor for

advanced glycation end products (RAGE), J. Biol. Chem. 279

(2004) 5059–5065.

[69] D.K. Chou, J. Zhang, F.I. Smith, P. McCaffery, F.B. Jungalwala,

Developmental expression of receptor for advanced glycation end

products (RAGE) amphoterin and sulfoglucuronyl (HNK-1) carbo-

hydrate in mouse cerebellum and their role in neurite outgrowth and

cell migration, J. Nerochem. 90 (2004) 1389–1401.


[70] B. Bartling, H.S. Hofmann, B. Weigle, R.E. Silber, A. Simm, Down-

regulation of the receptor for advanced glycation end-products

(RAGE) supports non-small cell lung carcinoma, Carcinogenesis 26

(2005) 293–301.

[71] D. Giugliano, G. Paolisso, A. Ceriello, Oxidative stress and diabetic

vascular complications, Diabetes Care 19 (1996) 257–267.

[72] R. Butler, A.D. Morris, J.J. Belch, A. Hill, A.D. Struthers,

Allopurinol normalizes endothelial dysfunction in type 2 diabetes

with mild hypertension, Hypertension 35 (2000) 746–751.

[73] G. O’Driscoll, D. Green, J. Rankin, K. Stanton, R. Taylor, Improve-

ment in endothelial function by angiotensin converting enzyme

inhibition in insulin-dependent diabetes mellitus, J. Clin. Invest. 100

(1997) 678–684.

[74] J. Bojunga, B. Dresar-Mayert, K.H. Usadel, K. Kusterer, S. Zeuzem,

Antioxidative treatment reverses imbalance of nitric oxide synthase

isoform expression and attenuates tissue-cGMP activation in diabetic

rats, Biochem. Biophys. Res. Commun. 316 (2004) 771–780.

[75] A.C. Maritim, R.A. Sanders, J.B Watkins III, Diabetes, oxidative

stress and antioxidants: a review, J. Biochem. Mol. Toxicol. 17

(2003) 24–38.

[76] J.S. Beckman, W.H. Koppenol, Nitric oxide, superoxide, and

peroxynitrite: the good, the bad, and ugly, Am. J. Physiol. 271

(1996) C1424–C1437.

[77] A. Ceriello, F. Mercuri, L. Quangliaro, R. Assaloni, E. Motz, L.

Tonutti, C. Taboga, Detection of nitrotyrosine in the diabetic plasma:

evidence of oxidative stress, Diabetologia 44 (2001) 834–838.

[78] A. Avogaro, F. Piarulli, A. Valerio, M. Miola, M. Calveri, P. Pavan, P.

Vicini, C. Cobelli, A. Tiengo, L. Calo, S. Del Prato, Forearm nitric

oxide balance, vascular relaxation, and glucose metabolism in

NIDDM patients, Diabetes 46 (1997) 1040–1046.

[79] L. Rodriguez-Manas, P. Lopez-Doriga, R. Petidier, M. Neira, J. Solis,

I. Pavon, C. Peiro, C.F. Sanchez-Ferrer, Effect of glycaemic control

on the vascular nitric oxide system in patients with type 1 diabetes,

J. Hypertens. 21 (2003) 1137–1143.

[80] T.J. Guzik, S. Mussa, D. Gastaldi, J. Sadowski, C. Ratnatunga, R.

Pillai, K.M. Channon, Mechanisms of increased vascular superoxide

production in human diabetes mellitus: role of NAD(P)H oxidase and

endothelial nitric oxide synthase, Circulation 105 (2002) 1656–1662.

[81] A.L. Bardell, K.M. MacLeod, Evidence for inducible nitric-oxide

synthase expression and activity in vascular smooth muscle of

streptozotocin-diabetic rats, J. Pharmacol. Exp. Ther. 296 (2001)

252–259.

[82] S. Vehkavaara, A. Seppala-Lindroos, J. Westerbacka, P.H. Groop, H.

Yki-Jarinen, In vivo endothelial dysfunction characterizes patients

with impaired fasting glucose, Diabetes Care 22 (1999) 2055–2060.

[83] H.O. Steinberg, H. Chaker, R. Leaming, A. Johnson, G. Brechtel,

A.D. Baron, Obesity/insulin resistance is associated with endothelial

dysfunction. Implications for the syndrome of insulin resistance,

J. Clin. Invest. 97 (1996) 2601–2610.

[84] L. Nathan, G. Chaudhuri, Estrogens and atherosclerosis, Annu. Rev.

Pharmacol. Toxicol. 37 (1997) 477–515.

[85] R. Xu, J.A. Morales, R. Muniyappa, D.F. Skafar, J.L. Ram, J.R.

Sowers, Interleukin-1beta-induced nitric oxide production in rat

aortic endothelial cells: inhibition by estradiol in normal and high

glucose cultures, Life. Sci. 64 (1999) 2451–2462.

[86] M.D. Kesim, Y. Aydin, M. Erdemir, A. Atis, Nitric oxide in

postmenopausal women taking the different HRT regimens,

Maturitas 50 (2005) 52–57.

[87] C. Bolego, A. Cignarella, V. Zancan, C. Pinna, R. Zanardo, L.

Puglisi, Diabetes abolishes the vascular protective effects of estrogen

in female rats, Life Sci. 64 (1999) 741–749.

[88] A. Maggi, A. Cignarella, A. Brusadelli, C. Bolego, C. Pinna, L.

Puglisi, Diabetes undermines estrogen control of inducible nitric

oxide synthase function in rat aortic smooth muscle cells through

overexpression of estrogen receptor-beta, Circulation 108 (2003)

211–217.

[89] P. Rosen, P.P. Nawroth, G. King, W. Moller, H.J. Trischler, L. Packer,

The role of oxidative stress in the onset and progression of diabetes

and its complications: a summary of a Congress Series sponsored by

UNESCO-MCBN, the American Diabetes Association and the Ger-

man Diabetes Society, DiabetesMetab. Res. Rev. 17 (2001) 189–212.

[90] M.A. Yorek, The role of oxidative stress in diabetic vascular and

neural disease, Free Radical Res. 37 (2003) 471–480.

[91] G.W. Small, Treatment of Alzheimer’s disease: current approaches

and promising developments, Am. J. Med. 104 (1998) 32S–38S.

[92] B. Moosmann, C. Behl, The antioxidant neuroprotective effects of

estrogens and phenolic compounds are independent from their

estrogenic properties, Proc. Natl. Acad. Sci. U. S. A. 96 (1999)

8867–8872.

[93] L. Prokai, K. Prokai-Tatrai, P. Perjesi, A.D. Zharikova, E.J. Perez, R.

Liu, J.W. Simpkins, Quinol based cyclic anti-oxidant mechanism in

estrogen neuroprotection, Proc. Natl. Acad. Sci. U.S.A. 100 (2003)

11741–11746.

[94] B.K. Yoon, W.J. Oh, B. Kessel, C.R. Roh, D. Choi, J.H. Lee, D.K.

Kim, 17 Beta-estradiol inhibits proliferation of cultured vascular

smooth muscle cells induced by lysophosphatidylcholine via a

nongenomic antioxidant mechanism, Menopause 8 (2001) 58–64.

[95] R.K. Dubey, Y.Y. Tyurina, V.A. Tyurin, D.G. Gillespie, R.A. Branch,

E.K. Jackson, V.E. Kagan, Estrogen and tamoxifen metabolites

protect smooth muscle cell membrane phospholipids against perox-

idation and inhibit cell growth, Circ. Res. 84 (1999) 229–239.

[96] F. Saravia, Y. Revsin, V. Lux-Lantos, J. Beauquis, J. Homc, F.

Dearche, A.F. De Nicola, Oestradiol restores cell proliferation in

dentate gyrus and subventicular zone of streptozotocin-diabetic mice,

BJ Neuroendocrinol. 16 (2004) 704–710.

[97] R.A. Santizo, H.L. Xu, S. Ye, V.L. Baughman, D. Pelligrino, Loss of

benefit from estrogen replacement therapy in diabetic ovarectomized

female rats subjected to transient forebrain ischemia, Brain Res. 956

(2002) 86–95.

[98] J.F. Arnal, S. Clamens, C. Pechet, A. Negre-Salvayre, C. Allera,

J.P. Girolami, R. Salvayre, F. Bayard, Ethinylestradiol does not

enhance the expression of nitric oxide in bovine endothelial cells

but increases the release of bioactive nitric oxide by inhibiting

superoxide anion production, Proc. Natl. Acad. Sci. U. S. A. 93

(1996) 4108–4113.

[99] S. Jain, D. Saxena, P.G. Kumar, S.S. Koide, M. Laloraya, Effect of

estradiol and selected antiestrogens on pro and antioxidant pathways

in mammalian uterus, Contraception 60 (1999) 111–118.

[100] H.S. Purba, J.L. Maggs, M.L. Orme, D.J. Back, B.K. Park, The

metabolism of 17alpha-ethinyloestradiol by human liver microsomes:

formation of catechol and chemically reactive metabolites, Br. J.

Clin. Pharmacol. 23 (1987) 447–453.

[101] J. Chen, M. Gokhale, Y. Li, M.A. Trush, J.D. Yager, Enhanced levels

of several mitochondrial transcripts and mitochondrial superoxide

production during ethinylestradiol-induced hepatocarcinogenesis and

after estrogen treatment of HepG2 cells, Carcinogenesis 19 (1998)

2187–2193.

[102] J. Rashba-Step, A.I. Cederabaum, Generation of reactive oxygen

intermediates by human liver microsomes in presence of NADPH or

NADH, Mol. Pharmacol. 45 (1994) 150–157.

[103] K.T. Shiverick, M. Notelovitz, Regulation of Cytochrome P-450

dependent catechol estrogen formation in rat liver microsomes.

Evidence for involvement of estrogen receptors, Biochem. Pharma-

col. 32 (1983) 2399–2403.

[104] G. Bednarek-Tupikowska, K. Tupikowski, B. Bidzinska, A. Bohda-

nowicz-Pawlak, J. Antonowicz-juchniewicz, B. Kosowska, A. Mile-

wicz, Serum lipid peroxidase and total antioxidant status in

postmenopausal women on hormone replacement therapy, Gynecol.

Endocrinol. 19 (2004) 57–63.

[105] M. Nazirouglu, M. Simsek, H. Simsek, N. Aydilek, Z. Ozcan, R.

Atilgan, The effect of hormone replacement therapy combined with

vitamin C and E on antioxidants levels and lipid profiles in

postmenopausal women with type 2 diabetes, Clin. Chim. Acta 344

(2004) 63–71.


[106] I. Bureau, F. Laporte, M. Favier, H. Faure, M. Fields, A.E. Favier,

A.M. Russel, No antioxidant effect of combined HRT on LDL

oxidizability and oxidative stress biomarkers in treated postmeno-

pausal women, J. Am. Coll. Nutr. 21 (2002) 333–338.

[107] D.D. Waters, E.L. Alderman, J. Hsia, B.V. Howard, F.R. Cobb, W.J.

Rogers, P. Ouayang, P. Thompson, J.C. Tardif, L. Higgis, V. Bittner,

M. Steffes, D.J. Gordon, M. Proschan, N. Younes, J.I. Verter, Effects

of hormonal replacement therapy and antioxidant vitamin supple-

ments on coronary atherosclerosis in postmenopausal women: a

randomized controlled trial, JAMA 288 (2002) 2432–2440.

[108] A. Ferrara, C.P. Quesenberry, A.J. Karter, C.W. Njoroge, A.S.

Jacobson, J.V. Selby, Northern California Kaiser Permanente

Diabetes Registry. Current use of unopposed estrogen and estro-

gen plus progestin and the risk of acute myocardial infarction

among women with diabetes: the Northern California Kaiser

Permanente Diabetes Registry 1995–1998, Circulation 107 (2003)

43–48.

[109] F. Grodstein, J.E. Manson, M.J. Stampfer, Postmenopausal hormone

use and secondary prevention of coronary events in the nurses’ health

study. A prospective, observational study, Ann. Intern. Med. 135

(2001) 1–8.

[110] A.M. Shearman, L.A. Cupples, S. Demissie, I. Peter, C.H. Scmid,

R.H. Karas, M.E. Mendelsohn, D.E. Housman, D. Levy, Association

between estrogen receptor alpha gene variation and cardiovascular

disease, JAMA 290 (2003) 2263–2270.

[111] T. Lehtimaki, R. Laaksonen, K.M. Mattila, T. Janatuinen, R.

Vesalainen, P. Nuutila, J. Laakso, O. Jaakkola, T. koivula, J.

Knuuti, Oestrogen receptor gene variation is a determinant of

coronary reactivity in healthy young men, Eur. J. Clin. Invest. 32

(2002) 400–404.

[112] D.M. Herrington, T.D. Howard, G.A. Hawkins, D.M. Reboussin, J.

Xu, S.L. Zheng, K.B. Brosnihan, D.A. Meyers, E.R. Bleecker,

Estrogen-receptor polymorphisms and effects of estrogen replace-

ment on high-density lipoprotein cholesterol in women with coronary

disease, N. Engl. J. Med. 346 (2002) 967–974.

[113] J.L. Turgeon, D.P. McDonnell, K.A. Martin, P.M. Wise, Hormone

therapy: Physiological complexity belies therapeutic simplicity,

Science 304 (2004) 1269–1273.

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