Certain Progestins Prevent the Enhancing Effect of 17β-Estradiol on NO-Mediated Inhibition of Platelet Aggregation by Endothelial Cells

Zerr-Fouineau, Murielle; Jourdain, Marie‐Laure; Boesch, C.; Hecker, Markus; Bronner, Christian; Schini‐Kerth, Valérie B.

doi:10.1161/atvbaha.108.178004

Cited by 34 publications

(21 citation statements)

References 61 publications

(48 reference statements)

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“…However, as E 2 convincingly reduces lipid oxidation and subcutaneous lipolysis, it is intuitively appealing that it should also reduce ATBF to regional fat depots. E 2 treatment was also associated with a significant increase in eNOS mRNA expression in muscle, an effect that has been demonstrated before in animal and cell studies (43,44). This may serve to further divert blood from adipose tissue toward muscle.…”

Section: Discussionsupporting

confidence: 65%

Estradiol acutely inhibits whole body lipid oxidation and attenuates lipolysis in subcutaneous adipose tissue: a randomized, placebo-controlled study in postmenopausal women

Gormsen

Høst²,

Hjerrild³

et al. 2012

European Journal of Endocrinology

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Context: Estradiol (E 2 ) promotes and maintains the female phenotype characterized by subcutaneous fat accumulation. There is evidence to suggest that this effect is due to increased anti-lipolytic a2A-adrenergic receptors, but whether this requires long-term exposure to E 2 or is an immediate effect is not clear. Objective: To study acute effects of a single dose (4 mg) of 17b-E 2 on regional and systemic lipolysis. Methods: Sixteen postmenopausal women (age, 59G5 years; weight, 67G10 kg; and BMI, 24.8G2.9) were studied in a crossover design: i) placebo and ii) 4 mg E 2 . Basal and adrenaline-stimulated regional lipolysis was assessed by microdialysis and substrate oxidation rates by indirect calorimetry. Tissue biopsies were obtained to assess lipoprotein lipase activity and mRNA expression of adrenergic, estrogen, cytokine, and vascular reactivity receptors. Results: Acute E 2 stimulation significantly attenuated catecholamine-stimulated lipolysis in femoral subcutaneous adipose tissue (interstitial glycerol concentration (micromole/liter) ANOVA time vs treatment interaction, PZ0.01) and lipolysis in general in abdominal adipose tissue (ANOVA treatment alone, P!0.05). E 2 also reduced basal lipid oxidation ((mg/kg per min) placebo, 0.58G0.06 vs E 2 , 0.45G0.03; PZ0.03) and induced a significantly higher expression of anti-lipolytic a2A-adrenergic receptor mRNA (PZ0.02) in skeletal muscle tissue as well as an upregulation of eNOS (NOS3) mRNA (PZ0.02). Conclusion: E 2 acutely attenuates the lipolytic response to catecholamines in subcutaneous adipose tissue, shifts muscular adrenergic receptor mRNA toward anti-lipolytic a2A-receptors, decreases whole body lipid oxidation, and enhances expression of markers of vascular reactivity.

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Section: Discussionsupporting

confidence: 65%

Estradiol acutely inhibits whole body lipid oxidation and attenuates lipolysis in subcutaneous adipose tissue: a randomized, placebo-controlled study in postmenopausal women

Gormsen

Høst²,

Hjerrild³

et al. 2012

European Journal of Endocrinology

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“…However, the outcomes are not exactly satisfactory, which are likely consequent to the fact that 1) H 4 B decays very quickly (9); and 2) overexpression of GTPCH1 has been found to only partially restore endothelial function in vivo (7). While sepiapterin also recouples eNOS effectively (15,43) in some studies, it failed to recouple eNOS in others (26,38,40), likely attributed to inhibited activity of salvage enzymes in vascular diseases. Although the rate-limiting salvage enzyme DHFR has been found to have a critical role in modulating eNOS coupling status and thus a therapeutic target (4), SPR, as an enzyme with dual actions in both H 4 B de novo synthesis and salvation, may also serve as a therapeutic approach, particularly in combination with sepiapterin supplementation.…”

Section: Discussionmentioning

confidence: 99%

Sepiapterin reductase regulation of endothelial tetrahydrobiopterin and nitric oxide bioavailability

Gao¹,

Pung

Zhang

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Sepiapterin reductase (SPR) catalyzes the final step of tetrahydrobiopterin (H(4)B) biosynthesis and the first step of H(4)B regeneration from an exogenous precursor sepiapterin. Despite the potential significance of SPR in regulating H(4)B-dependent nitric oxide (NO(*)) production, the endothelium-specific sequence and functions of SPR remain elusive. We first cloned endothelial SPR cDNA from bovine aortic endothelial cells (Genebank: DQ978331). In cells transiently transfected with SPR gene, SPR activity (HPLC) was dramatically increased by 19-fold, corresponding to a significant increase in endothelial H(4)B content (HPLC) and NO(*) production (electron spin resonance). In vivo delivery of SPR gene significantly increased vascular SPR protein expression (mouse vs. bovine antibodies to differentiate endogenous vs. exogenous), activity, H(4)B content, and NO(*) production, as well as NO(*)-dependent vasorelaxation. In endothelial cells transfected with small interfering RNA specific for SPR, approximately 87% of mRNA were attenuated (real-time quantitative RT-PCR), corresponding to a significant reduction in SPR protein expression and activity, which was associated with decreases in both intracellular H(4)B content and NO(*) level. Exogenous administration of sepiapterin to endothelial cells significantly upregulated H(4)B and NO(*) levels, which were attenuated by SPR RNA interference (RNAi). H(4)B-stimulated increase in NO(*) production, however, was SPR RNAi independent. GTP cyclohydrolase 1 expression and activity, as well as dihydrofolate reductase expression, were not affected by SPR RNAi, whereas dihydrofolate reductase activity was significantly downregulated. These data represent the first to study endothelial SPR functionally and clearly demonstrate an important role of endothelial SPR in modulating H(4)B and NO(*) bioavailability.

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“…In vitro studies have examined the interactions of a series of progestins on 17-beta estradiol (E 2 )-induced nitric oxide (NO) mediated inhibition of platelet aggregation by endothelial cells. 79,80 Some progestogens (e.g., progesterone and medroxyprogesterone acetate) reduced the beneficial actions of E 2 on NO formation, whereas others (e.g., nomegestrol acetate and levonorgestrel) did not negate this effect.…”

Section: Hemostasismentioning

confidence: 99%

Tailoring Combination Oral Contraceptives to the Individual Woman

Archer

Lasa

2011

Journal of Women's Health

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Certain Progestins Prevent the Enhancing Effect of 17β-Estradiol on NO-Mediated Inhibition of Platelet Aggregation by Endothelial Cells

Abstract: Certain progestins, including MPA, attenuate the 17beta-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells through preventing both eNOS and GTPCH I expression most likely via activation of glucocorticoid receptors.

Cited by 34 publications

References 61 publications

Estradiol acutely inhibits whole body lipid oxidation and attenuates lipolysis in subcutaneous adipose tissue: a randomized, placebo-controlled study in postmenopausal women

Estradiol acutely inhibits whole body lipid oxidation and attenuates lipolysis in subcutaneous adipose tissue: a randomized, placebo-controlled study in postmenopausal women

Sepiapterin reductase regulation of endothelial tetrahydrobiopterin and nitric oxide bioavailability

Tailoring Combination Oral Contraceptives to the Individual Woman

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