Short-term Anti-Ischemic Effect of 17β-Estradiol in Postmenopausal Women With Coronary Artery Disease

Rosano, Giuseppe; Caixeta, Adriano; Chierchia, Sergio; Arie, S; Lopez-Hidalgo, Miguel; Pereira, Wagner I.; Leonardo, Filippo; Webb, Carolyn; Pileggi, F; Collins, Peter

doi:10.1161/01.cir.96.9.2837

Cited by 36 publications

(20 citation statements)

References 31 publications

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“…We observed effects of 17␤-estradiol within 5-15 min, suggesting an acute, nongenomic action. Clinical studies have demonstrated that such acute exposure to estrogen relieves myocardial ischemia (1,34) and increases coronary blood flow (33) in patients with established CAD and/or intimal dysfunction. Therefore, the present findings provide a molecular mechanism that can at least partially explain how estrogen enhances coronary blood flow via a NO-dependent, endothelium-independent mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…This direct effect of estrogen on HCASMC may be an important mechanism for helping to counteract pathological coronary vasoconstriction in arteries with a damaged or diseased intima, as evidenced by clinical studies demonstrating that acute (15-30 min) administration of estrogen to postmenopausal women with CAD relieves myocardial ischemia (1,34) and increases coronary blood flow (33). At present, however, we know very little of how estrogen directly relaxes human CASM, especially in arteries with a dysfunctional endothelium.…”

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confidence: 99%

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Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling

Han

Chintala

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Sex steroids exert profound and controversial effects on cardiovascular function. For example, estrogens have been reported to either ameliorate or exacerbate coronary heart disease. Although estrogen dilates coronary arteries from a variety of species, the molecular basis for this acute, nongenomic effect is unclear. Moreover, we know very little of how estrogen affects human coronary artery smooth muscle cells (HCASMC). The purpose of this study was to elucidate nongenomic estrogen signal transduction in HCASMC. We have used tissue (arterial tension studies), cellular (single-channel patch clamp, fluorescence), and molecular (protein expression) techniques to now identify novel targets of estrogen action in HCASMC: type I (neuronal) nitric oxide synthase (nNOS) and phosphatidylinositol 3-kinase (PI3-kinase)Akt. 17beta-Estradiol (E(2)) increased NO-stimulated fluorescence in HCASMC, and cell-attached patch-clamp experiments revealed that stimulation of nNOS leads to increased activity of calcium-activated potassium (BK(Ca)) channels in these cells. Furthermore, overexpression of nNOS protein in HCASMC greatly enhanced BK(Ca) channel activity. Immunoblot studies demonstrated that E(2) enhances Akt phosphorylation in HCASMC and that wortmannin, an inhibitor of PI3-kinase, attenuated E(2)-stimulated channel activity, NO production, Akt phosphorylation, and estrogen-stimulated coronary relaxation. These studies implicate the PI3-kinase/Akt signaling axis as an estrogen transduction component in vascular smooth muscle cells. We conclude, therefore, that estrogen opens BK(Ca) channels in HCASMC by stimulating nNOS via a transduction sequence involving PI3-kinase and Akt. These findings now provide a molecular mechanism that can explain the clinical observation that estrogen enhances coronary blood flow in patients with diseased or damaged coronary arteries.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling

Han

Chintala

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…A large body of evidence suggests that estrogens inhibit the progression of atherosclerosis and have a important effects in the maintenance of arterial hemodynamics [2]. Short-term administration of 17β-estradiol has been shown to improve coronary and peripheral blood flow during exercise-induced myocardial ischemia in postmenopausal females with coronary artery disease [3,4]. These effects involve a number of mechanisms, including endothelium-derived nitric oxide production and release [5,6], and direct vascular smooth muscle relaxation by modulation of ion channels [7,8].…”

Section: Introductionmentioning

confidence: 99%

Acute administration of 17β-estradiol reduces endothelin-1 release during pacing-induced ischemia

Rosano¹,

Gebara²,

Sheiban³

et al. 2007

International Journal of Cardiology

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“…Furthermore, recent evidence suggests that estrogen has direct effects on cardiac myocytes. These cardiovascular actions may contribute to the observations in population-based studies of a reduced risk of cardiovascular disease faced by premenopausal women compared with age-matched men, and of the increase in incidence of coronary artery disease after menopause.Estrogen has been observed to play a role in the pathogenesis of left ventricular hypertrophy [1][2][3]; attenuation of contractile function [4]; reduction of myocardial ischemic injury [5,6]; and the reduction of incidence of ventricular arrhythmias in experimental models of regional ischemia-reperfusion [7,8]. Estrogen is classically understood to act via its steroid receptor, chiefly in the nucleus.…”

mentioning

confidence: 99%

“…Estrogen has been observed to play a role in the pathogenesis of left ventricular hypertrophy [1][2][3]; attenuation of contractile function [4]; reduction of myocardial ischemic injury [5,6]; and the reduction of incidence of ventricular arrhythmias in experimental models of regional ischemia-reperfusion [7,8]. Estrogen is classically understood to act via its steroid receptor, chiefly in the nucleus.…”

mentioning

confidence: 99%

17β-Estradiol Potentiates the Cardiac Cystic Fibrosis Transmembrane Conductance Regulator Chloride Current in Guinea-pig Ventricular Myocytes

Goodstadt¹,

Powell

Figtree

2006

J. Physiol. Sci

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There is a well-characterized membrane chloride current (I Cl,cAMP ) in the heart that can be activated by β-adrenergic agonists and is due to expression of the cardiac isoform of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR). We have investigated whether 17β-estradiol (E2) modulates I Cl,cAMP in single ventricular myocytes. Under whole-cell tight-seal voltage-clamp conditions, I Cl,cAMP was evoked by exposing cells to 20 nM isoprenaline. On the addition of 30 µM E2, membrane slope conductance, measured at potentials near 0 mV, increased over that induced by isoprenaline alone by 2.46 ± 0.16 (p < 0.001). The effects of E2 were concentration-dependent and described by a Hill Plot with an EC 50 of 8.2 µM and a Hill coefficient of 1.63. The application of membrane-impermeant E2 conjugated to bovine serum albumin (E2-BSA) potentiated isoprenaline-evoked I Cl,cAMP by approximately the same degree as that for the equivalent level of free E2. Cell surface binding was observed with confocal microscopy by using BSA-FITC tagged E2. This binding was inhibited by nonlabeled, nonconjugate E2, the specific E2 antagonist ICI 182,780, and incubation of E2coBSA with a specific anti-E2 antibody (E2885). ICI 182,780 (100 µM) significantly reduced the increase in I Cl,cAMP evoked by 10 µM E2 to 1.46 ± 0.10 (p < 0.02). The preincubation of myocytes with the NOS inhibitor N-ω-nitro-arginine (L-NNA, 1 mM) reduced the potentiation of I Cl,cAMP by 30 µM E2, to 1.93 ± 0.06 (p < 0.02), and for 10 µM E2, to 1.32 ± 0.05 (p < 0.002). E2 also increased I Cl,cAMP evoked by bath application of 0.5 µM Forskolin. These experiments demonstrate that, under our experimental conditions, E2 dramatically increases I Cl,cAMP in ventricular myocytes by mechanisms involving a contribution by NOS, but that can be only partially accounted for through binding to classical plasma membrane estrogen receptor sites. This potentiation of I Cl,cAMP by E2 may play a significant role in the observed clinical actions of E2 on the incidence of cardiac arrhythmias and hypertrophy.Key words: estrogen, cardiac myocyte, CFTR anion current.Responses to estrogen are observed in a diverse range of important systems, impacting the growth and function of breast and uterine tissue and bone homeostasis in both males and females. Cardiovascular actions are thought to include benefits to plasma cholesterol levels and vasomotor function. Furthermore, recent evidence suggests that estrogen has direct effects on cardiac myocytes. These cardiovascular actions may contribute to the observations in population-based studies of a reduced risk of cardiovascular disease faced by premenopausal women compared with age-matched men, and of the increase in incidence of coronary artery disease after menopause.Estrogen has been observed to play a role in the pathogenesis of left ventricular hypertrophy [1][2][3]; attenuation of contractile function [4]; reduction of myocardial ischemic injury [5,6]; and the reduction of incidence of ventricular arrhythmias in ...

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Short-term Anti-Ischemic Effect of 17β-Estradiol in Postmenopausal Women With Coronary Artery Disease

Cited by 36 publications

References 31 publications

Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling

Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling

Acute administration of 17β-estradiol reduces endothelin-1 release during pacing-induced ischemia

17β-Estradiol Potentiates the Cardiac Cystic Fibrosis Transmembrane Conductance Regulator Chloride Current in Guinea-pig Ventricular Myocytes

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