Bridging advanced glycation end product, receptor for ... - Core

Biochimica et Biophysica Acta 1745 (2005) 145 – 155 http://www.elsevier.com/locate/bba

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 antiinflammatory 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 * Corresponding author. Tel.: +1 801 581 7806; fax: +1 801 585 3355. E-mail address: [email protected] (T.K. Mukherjee). 0167-4889/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2005.03.010

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 abrogates 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

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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 ET on 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 premenopausal 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 endothelium-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 premenopausal 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 streptozotocininduced diabetic rats, estrogen treatment induces the generation 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-isoPGF2a 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 postmenopausal 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

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our group indicates that estrogens might inhibit atherosclerosis 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 responsible 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 bioavailability 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 nonenzymatic 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

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events lead in time to a broad array of proinflammatory complications in both macrovessel and microvessel structures, 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 molecules, 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. Surprisingly, 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 inflammation, evaluating the role of RAGE/sRAGE in diabetic animal models is essential.

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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 numerous target genes, such as tissue factor (TF) [64], vascular cell adhesion molecule-1 (VCAM-1) [65], p21Ras, extracellular 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 proinflammatory 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 oxidoreductases 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 expression 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 estrogens 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 complications 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 experiments 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

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mation and prooxidation. Administration of synthetic estrogens 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

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-

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 mechanisms [75] and react with molecular nitric oxide to generate

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.

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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

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 activation and , 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

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]. Therefore, 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

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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 molecules in turn further induce the generation of ROS through the activation of the mitochondrial respiratory chain and NADPH 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 longterm 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 estrogendependent protection against neurological disorders [91 – 93] and inhibition of smooth muscle cell proliferation [94,95]. Of note, inhibition of smooth muscle cell proliferation 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 vitamins 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 postmenopausal 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

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treatment [107]. The exact reason for the failure of HRT or antioxidant vitamin treatment to protect the cardiovasculature 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 estrogen. 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 determinant of cardiovascular complications [110– 112]. In addition, 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. Alterations 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 complications [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, Menopause 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

152

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14] [15] [16]

[17]

[18]

[19]

[20] [21]

[22]

S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145 – 155 randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors, J. Intern. Med. 249 (2001) 237 – 246. 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. L. Mosca, The role of hormone replacement therapy in the prevention of postmenopausal heart disease, Arch. Intern. Med. 160 (2000) 2263 – 2272. C.D. Furberg, B.M. Psaty, Review: hormone replacement therapy may reduce the risk for death in younger but not older postmenopausal women, ACP J. Club 142 (2005) 1. M.J. Stampfer, G.A. Colditz, Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence, Prev. Med. 20 (1991) 47 – 63. 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. J. Waltenberger, Impaired collateral vessel development in diabetes: potential cellular mechanism and therapeutic implications, Cardiovasc. Res. 49 (2001) 554 – 560. 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. 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. 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. 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. J.M. Orshal, R.A. Khalil, Gender, sex hormones and vascular tone, Am. J. Physiol., Comp. Physiol. 286 (2004) R233 – R249. J. Thompson, R.A. Khalil, Gender differences in the regulation of vascular tone, Clin. Exp. Pharmacol. Physiol. 30 (2003) 1 – 15. 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 postmenopausal women, Am. J. Obstet. Gynecol. 161 (1989) 1677 – 1681. 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. 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. 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. V. Brezinka, I. Padmos, Coronary heart disease risk factors in women, Eur. Heart J. 15 (1994) 1571 – 1584. 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. 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

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33] [34]

[35]

[36]

[37]

[38]

infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis, J. Am. Coll. Cardiol. 14 (1989) 49 – 57. 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. 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. 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. W. Cefalu, The use of hormone replacement therapy in postmenopausal women with type 2 diabetes, J. Women’s Health Gend. Based Med. 10 (2001) 241 – 255. 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. 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. 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. 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. 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. 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. S.B. Hulley, D. Grady, The WHI estrogen-alone trial—Do things look any better? JAMA 291 (2004) 1769 – 1771. 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. 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. 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. 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 atherosclerosis, Circ. Res. 84 (1999) 489 – 497. 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.

S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145 – 155

[39]

[40]

[41]

[42]

[43]

[44]

[45] [46] [47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

Thorpe, M.E. Cooper, T.J. Allen, Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis, Diabetes 53 (2004) 1813 – 1823. 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. 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 atherosclerosis by the soluble receptor for advanced glycation endproducts, Nat. Med. 4 (1998) 1025 – 1031. 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. 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. 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. 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. M. Brownlee, Advanced protein glycosylation in diabetes and aging, Annu. Rev. Med. 46 (1995) 223 – 234. A.M. Schmidt, S.D. Yan, D.M. Stern, The dark side of glucose, Nat. Med. 1 (1995) 1002 – 1004. 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. 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. R. Bucala, K.J. Tracey, A. Cerami, AGEs quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes, J. Clin. Invest. 87 (1991) 432 – 438. 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. 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, Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes, Diabetes 48 (1999) 1856 – 1862. 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. 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. 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. 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. 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

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

153

RAGE dependent neointimal expansion in arterial restenosis, J. Clin. Invest. 111 (2003) 959 – 972. 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. 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. 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. 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. 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. 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. 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. 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. 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 vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice: a potential mechanism for the accelerated vasculopathy of diabetes, J. Clin. Invest. 96 (1995) 1395 – 1403. 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. 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. 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. 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) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration, J. Nerochem. 90 (2004) 1389 – 1401.

154

S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145 – 155

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

[90] [91] [92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

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 German Diabetes Society, Diabetes Metab. Res. Rev. 17 (2001) 189 – 212. M.A. Yorek, The role of oxidative stress in diabetic vascular and neural disease, Free Radical Res. 37 (2003) 471 – 480. G.W. Small, Treatment of Alzheimer’s disease: current approaches and promising developments, Am. J. Med. 104 (1998) 32S – 38S. 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. 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. 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. 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 peroxidation and inhibit cell growth, Circ. Res. 84 (1999) 229 – 239. 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. 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. 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. 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. 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. 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. 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. 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. Pharmacol. 32 (1983) 2399 – 2403. G. Bednarek-Tupikowska, K. Tupikowski, B. Bidzinska, A. Bohdanowicz-Pawlak, J. Antonowicz-juchniewicz, B. Kosowska, A. Milewicz, Serum lipid peroxidase and total antioxidant status in postmenopausal women on hormone replacement therapy, Gynecol. Endocrinol. 19 (2004) 57 – 63. 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.

S. Mukhopadhyay, T.K. Mukherjee / Biochimica et Biophysica Acta 1745 (2005) 145 – 155 [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 postmenopausal 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 supplements 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 estrogen 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

[110]

[111]

[112]

[113]

155

study. A prospective, observational study, Ann. Intern. Med. 135 (2001) 1 – 8. 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. 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. 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 replacement on high-density lipoprotein cholesterol in women with coronary disease, N. Engl. J. Med. 346 (2002) 967 – 974. J.L. Turgeon, D.P. McDonnell, K.A. Martin, P.M. Wise, Hormone therapy: Physiological complexity belies therapeutic simplicity, Science 304 (2004) 1269 – 1273.