Postmenopausal hormone replacement therapy increases plasmatic thromboxane β2

Oliveira, Rute Loreto S.; Aldrighi, José Mendes; Gebara, Otávio; Rocha, Tânia Rúbia Flores da; D'Ámico, Elbio Antônio; Rosano, Giuseppe; Ramires, José Antônio Franchini

doi:10.1016/j.ijcard.2004.10.009

Cited by 15 publications

(7 citation statements)

References 26 publications

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“…Moreover, the ratio of in vivo PGI2 to TXA2 formation increased twofold during estrogen replacement therapy (Mueck et al 2001). Nevertheless, it has also been documented that estrogen increases platelet activation with the liberation of TXA2 in women treated with hormone replacement therapy (Oliveira et al 2005), and that estrogen enhances the constrictor prostanoid function in female rat aorta (Li et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α

Sobrino¹,

Oviedo²,

Novella³

et al. 2010

Journal of Molecular Endocrinology

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Estradiol (E 2 ) acts on the endothelium to promote vasodilatation through the release of several compounds, including prostanoids, which are products of arachidonic acid metabolism. Among these, prostacyclin (PGI2) and thromboxane A2 (TXA2) exert opposite effects on vascular tone. The role of different estrogen receptors (ERs) in the PGI2/TXA2 balance, however, has not been fully elucidated. Our study sought to uncover whether E 2 enhances basal production of PGI2 or TXA2 in cultured human umbilical vein endothelial cells (HUVECs), to analyze the enzymatic mechanisms involved, and to evaluate the different roles of both types of ERs (ERa and ERb). HUVECs were exposed to E 2 , selective ERa (1,3,5-tris(4-hydroxyphenyl)-4-propyl-1h-pyrazole, PPT) or ERb (diarylpropionitrile, DPN) agonists and antagonists (unspecific: ICI 182 780; specific for ERa: methyl-piperidino-pyrazole, MPP). PGI2 and TXA2 production was measured by ELISA. Expression of phospholipases, cyclooxygenases (COX-1 and COX-2), PGI2 synthase (PGIS), and thromboxane synthase (TXAS) was analyzed by western blot and quantitative RT-PCR. E 2 (1-100 nM) dose dependently increased PGI2 production (up to 50%), without affecting TXA2 production. COX-1 and PGIS protein and gene expressions were increased, whereas COX-2, phospholipases, and TXAS expression remained unaltered. All these effects were mediated through ERa, since they were produced not only in the presence of E 2 , but also in that of PPT, while they were abolished in the presence of MPP. In conclusion, E 2 , acting through ERa, up-regulates COX-1 and PGIS expression, thus directing prostanoid balance toward increased PGI2 production.

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Section: Discussionmentioning

confidence: 99%

Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α

Sobrino¹,

Oviedo²,

Novella³

et al. 2010

Journal of Molecular Endocrinology

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“…Platelet hyperactivity is a critical contributor to the increased risk for cardiovascular diseases observed in postmenopausal women. 24 In this study, we demonstrated that supplementing postmenopausal women with ω‐3 or ω‐6 PUFAs attenuated platelet reactivity. Previously, the Women's Health Initiative study showed that increased ω‐3 phospholipid levels in the plasma of postmenopausal women were associated with lower risk of coronary heart disease.…”

Section: Discussionmentioning

confidence: 60%

“… 30 , 31 The data presented here supports that supplementing postmenopausal women with ω‐3 or ω‐6 fatty acids attenuates their basal platelet hyperactivity state. 24 Furthermore, we have demonstrated that post‐washout agonist‐induced αIIbβ3 activation was attenuated following supplementation with fish oil or primrose oil. Taken together, these findings suggest that supplementation with ω‐3 or ω‐6 fatty acids may further contribute to lowering the chronic risk of a thrombotic event leading to myocardial infarction or stroke in postmenopausal women.…”

Section: Discussionmentioning

confidence: 93%

Supplementation with omega‐3 or omega‐6 fatty acids attenuates platelet reactivity in postmenopausal women

Yamaguchi

Stanger

Freedman

et al. 2022

Clinical Translational Sci

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Postmenopausal women are at increased risk for a cardiovascular event due to platelet hyperactivity. There is evidence suggesting that ω‐3 polyunsaturated fatty acids (PUFAs) and ω‐6 PUFAs have cardioprotective effects in these women. However, a mechanistic understanding of how these fatty acids regulate platelet function is unknown. In this study, we supplemented postmenopausal women with fish oil (ω‐3 fatty acids) or evening primrose oil (ω‐6 fatty acids) and investigated the effects on their platelet activity. The effects of fatty acid supplementation on platelet aggregation, dense granule secretion, and activation of integrin αIIbβ3 at basal levels and in response to agonist were tested in postmenopausal women following a supplementation and washout period. Supplementation with fish oil or primrose oil attenuated the thrombin receptor PAR4‐induced platelet aggregation. Supplementation with ω‐3 or ω‐6 fatty acids decreased platelet dense granule secretion and attenuated basal levels of integrin αIIbβ3 activation. Interestingly, after the washout period following supplementation with primrose oil, platelet aggregation was similarly attenuated. Additionally, for either treatment, the observed protective effects post‐supplementation on platelet dense granule secretion and basal levels of integrin activation were sustained after the washout period, suggesting a long‐term shift in platelet reactivity due to fatty acid supplementation. These findings begin to elucidate the underlying mechanistic effects of ω‐3 and ω‐6 fatty acids on platelet reactivity in postmenopausal women. Hence, this study supports the beneficial effects of fish oil or primrose oil supplementation as a therapeutic intervention to reduce the risk of thrombotic events in postmenopausal women. https://clinicaltrials.gov/ct2/show/NCT02629497.

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“…Augmented TXA 2 production was previously reported in intact six months old SAMP8 female mice, and nonspecific COX inhibition corrected this parameter [29]. In postmenopausal women, estrogen increases platelet activation via TXA 2 production [42]. In contrast, another study demonstrated that estrogen does not change TXA 2 production in cultured human endothelial cells [43].…”

Section: Discussionmentioning

confidence: 80%

Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ERα36

Costa

Jiménez‐Altayó

Echem

et al. 2019

Cells

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Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women’s age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17β-estradiol starting at the day of ovariectomy (early-onset, E2E) or 45 days after surgery (late-onset, E2L). In SAMR1, both treatments, E2E and E2L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2E: 128.1 ± 11.6; E2L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2E: 183.3 ± 11.1; E2L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA.

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Postmenopausal hormone replacement therapy increases plasmatic thromboxane β2

Cited by 15 publications

References 26 publications

Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α

Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α

Supplementation with omega‐3 or omega‐6 fatty acids attenuates platelet reactivity in postmenopausal women

Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ERα36

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