Estrogen therapy replenishes vascular tetrahydrobiopterin and reduces oxidative stress in ovariectomized rats

Lam, Kwok Keung; Lee, Yen-Mei; Hsiao, George; Chen, Shu Ying; Yen, Mao‐Hsiung

doi:10.1097/01.gme.0000182806.99137.5e

Cited by 50 publications

(37 citation statements)

References 31 publications

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“…More recent studies have also pointed to the capacity of estrogens to increase availability of BH 4 [49] and also to the capacity of NO and SOD-1 to account for reduced neointimal hyperplasia in female mice [50]. The molecular mechanisms behind the observed differences in our study were not explored.…”

Section: Espinosa-díez Et Alcontrasting

confidence: 38%

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

Espinosa

Miguel

Vallejo

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C TGlutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The ratelimiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH 4 . To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.

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Section: Espinosa-díez Et Alcontrasting

confidence: 38%

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

Espinosa

Miguel

Vallejo

et al. 2017

Free Radical Biology and Medicine

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“…Furthermore, oxidative stress is higher in postmenopausal women than in premenopausal women (69), which is also consistent with higher blood pressure levels in postmenopausal women (5). These data support the concept that estradiol has antioxidant properties, since estradiol can reduce expression of NADPH oxidase subunits and increase expression of superoxide dismutase (4,31,38,43). However, the studies of the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study trials have not supported a protective role for estradiol in either primary or secondary cardiovascular disease (6,16,22,45).…”

Section: Oxidative Stress and Hypertension In Humans: Clinical Trialsmentioning

confidence: 76%

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

Lopez‐Ruiz¹,

Sartori‐Valinotti²,

Yanes³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Lopez-Ruiz A, Sartori-Valinotti J, Yanes LL, Iliescu R, Reckelhoff JF. Sex differences in control of blood pressure: role of oxidative stress in hypertension in females. Am J Physiol Heart Circ Physiol 295: H466 -H474, 2008. First published June 20, 2007 doi:10.1152/ajpheart.01232.2007.-In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women.F 2-isoprostanes WITH THE USE OF AMBULATORY blood pressure monitoring, it is now well accepted that blood pressure is higher in men than age-matched premenopausal women, and that, following menopause, this trend reverses, such that the incidence of hypertension in postmenopausal women is similar to or higher than in men (5, 69). A comparison of the data from the National Health and Nutrition Examination Survey (NHANES) III (1988III ( -1994 with data from NHANES IV (1999 -2002) revealed that the prevalence of hypertension is currently stable in men, and their blood pressures are well controlled with medication. In contrast, in women, the incidence of hypertension is progressively increasing, and blood pressure is often higher in women than in age-matched men (35). Furthermore, blood pressure in women is not well controlled with medication, despite typically higher levels of compliance compared with men (35). These disturbing statistics suggest that mechanisms responsible for hypertension in men and women may be different, and it is imperative that physicians and scientists begin to determine what these differences are to better treat hypertension in both men and women. Oxidative Stress and Hypertension in Humans: Clinical TrialsThe role that oxidative stress plays in mediating hypertension has been the focus of a significant amount of research in recent years. Several clinical trials have be...

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“…Alternatively, the inhibition of nNOS in the OVXmRen2.Lewis rat to reduce blood pressure may reflect the suppression of NO-dependent pressor metabolites, such as peroxynitrite or other reactive oxygen species (ROS). Tetrahydrobiopterin (BH4), an estrogen-sensitive cofactor for NOS (35), is essential for NO generation, and reduced BH4 may lead to enhanced levels of superoxide products (23,24,32,37,42). Clearly, additional studies are required to address whether increased NO or nNOS-derived ROS in the kidney (or other tissue sites) contributes to the sustained hypertensive response to estrogen depletion in the mRen2.Lewis strain.…”

Section: Discussionmentioning

confidence: 99%

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

Yamaleyeva¹,

Gallagher²,

Vinsant³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Yamaleyeva LM, Gallagher PE, Vinsant S, Chappell MC. Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats. Am J Physiol Regul Integr Comp Physiol 292: R819 -R826, 2007. First published October 5, 2006; doi:10.1152/ajpregu.00389.2006.-Estrogen depletion markedly exacerbates hypertension in female congenic mRen2.Lewis rats, a model of tissue renin overexpression. Because estrogen influences nitric oxide synthase (NOS) and NO may exert differential effects on blood pressure, the present study investigated the functional expression of NOS isoforms in the kidney of ovariectomized (OVX) mRen2.Lewis rats. OVX-mRen2.Lewis exhibited an increase in systolic blood pressure (SBP) of 171 Ϯ 5 vs. 141 Ϯ 7 mmHg (P Ͻ 0.01) for intact littermates. Renal cortical mRNA and protein levels for endothelial NOS (eNOS) were reduced 50 -60% (P Ͻ 0.05) and negatively correlated with blood pressure. In contrast, cortical neuronal NOS (nNOS) mRNA and protein levels increased 100 to 300% (P Ͻ 0.05). In the OVX kidney, nNOS immunostaining was more evident in the macula densa, cortical tubules, and the medullary collecting ducts compared with the intact group. To determine whether the increase in renal nNOS expression constitutes a compensatory response to the reduction in renal eNOS, we treated both intact and OVX mRen2.Lewis rats with the selective nNOS inhibitor L-VNIO from 11 to 15 wk of age. The nNOS inhibitor reduced blood pressure in the OVX group (185 Ϯ 3 vs. 151 Ϯ 8 mmHg, P Ͻ 0.05), but pressure was not altered in the intact group (146 Ϯ 4 vs. 151 Ϯ 4 mmHg). In summary, exacerbation of blood pressure in the OVX mRen2.Lewis rats was associated with the discoordinate regulation of renal NOS isoforms. Estrogen sensitivity in this congenic strain may involve the influence of NO through the regulation of both eNOS and nNOS. endothelial nitric oxide synthase; estrogen; hypertension; aldosterone; angiotensin II; renin THE PROTECTIVE ROLE OF ESTROGEN in cardiovascular disease remains a highly controversial and complex area of study, particularly given the recent findings of the Women's Health Initiative (WHI) study. Although experimental and clinical data support the beneficial actions of estrogen, both the WHI and the Heart and Estrogen Replacement Study follow-up (HERS II) studies concluded that there was no cardioprotective benefit for estrogen replacement in older women with underlying cardiovascular disease (19, 39). Indeed, the incidence for ischemic stroke and dementia were higher for this population of postmenopausal women receiving either estrogen or combined hormone replacement therapy (40, 41). The results of WHI and HERS were surprising, in part, due to the generally accepted view that estrogen has beneficial actions on nitric oxide (NO), as well as an inhibitory influence on the components of the renin-angiotensin-aldosterone system (RAAS), including ACE and the angiotensin type 1 (AT1) receptor (6,12,17,26,33,45).Our studies in the congenic mRen2.Lewis strain of hypertensive rats ...

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Estrogen therapy replenishes vascular tetrahydrobiopterin and reduces oxidative stress in ovariectomized rats

Abstract: ET increases the availability of vascular BH4 to attenuate O2. production and restores total antioxidant capacity, leading to improved NO-mediated vasodilation in Ovx rats.

Cited by 50 publications

References 31 publications

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

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