Modulation of hypertensive heart disease by estrogen

Grohé, Christian; Kahlert, Stefan; Löbbert, Kerstin; Meyer, Rainer; Linz, Klaus; Karas, Richard H.; Vetter, Hans

doi:10.1016/0039-128x(96)00014-1

Cited by 46 publications

(28 citation statements)

References 17 publications

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“…The profound inhibition of I Ca,L by raloxifene over the range of potentials tested is similar to previously documented direct actions of 17b-oestradiol on cardiac myocytes (Jiang et al, 1992;Grohe et al, 1996;Nakajima et al, 1999a). However, raloxifene did not significantly shift the steady-state activation or inactivation curves.…”

Section: Discussionsupporting

confidence: 87%

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Liew

Stagg

MacLeod

et al. 2004

British J Pharmacology

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1 The selective oestrogen (ER) receptor modulator, raloxifene, is widely used in the treatment of postmenopausal osteoporosis, but may also possess cardioprotective properties. We investigated whether it directly suppresses myocyte contractility through Ca 2 þ channel antagonism in a similar way to 17b-oestradiol. 2 Cell shortening and Ca 2 þ transients were measured in single guinea-pig ventricular myocytes fieldstimulated (1 Hz, 371C) in a superfusion chamber. Electrophysiological recordings were performed using single electrode voltage-clamp. 3 Raloxifene decreased cell shortening (EC 50 2.4 mM) and the Ca 2 þ transient amplitude (EC 50 6.4 mM) in a concentration-dependent manner. At a concentration of 1 mM, raloxifene produced a 3372% (mean7s.e.m) and 2472% reduction, respectively (Po0.001, n ¼ 14 for both parameters). 4 These inhibitory actions were not observed in myocytes that had been incubated with the specific antagonist, ICI 182,780 (10 mM) (n ¼ 11). 5 Raloxifene (1 mM) shortened action potential durations at 50 and 90% repolarisation (Po0.05 and o0.001, respectively; n ¼ 27) and decreased peak L-type Ca 2 þ current by 45%, from À5.170.5 pA/pF to À2.870.3 pA/pF (Po0.001, n ¼ 18). 6 Raloxifene did not significantly alter sarcoplasmic reticulum Ca 2 þ content, as assessed by integrating the Na þ /Ca 2 þ exchanger currents following rapid caffeine application. 7 The present study provides evidence for direct inhibitory actions of raloxifene on ventricular myocyte contractility, mediated through Ca 2 þ channel antagonism.

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Section: Discussionsupporting

confidence: 87%

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Liew

Stagg

MacLeod

et al. 2004

British J Pharmacology

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“…ERs are expressed in vascular smooth muscle cells, cardiac myocytes, and cardiac fibroblasts. 38 However, whereas estrogen was found previously to inhibit collagen synthesis in cultured cardiac fibroblasts, 39 E 2 treatment enhanced myocardial infarction-induced cardiac fibrosis in mice. 40 Whether estrogen exerts protective or detrimental effects on the heart may thus depend on the dose and on animal species and strain.…”

Section: Discussionmentioning

confidence: 93%

Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z- Lepr ^fa /Lepr ^fa Rats as a New Animal Model of Metabolic Syndrome

Murase

Hattori²,

Ohtake³

et al. 2012

Hypertension

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Abstract-Although recent clinical trials have found an increased incidence of cardiovascular disease in women on estrogen replacement therapy, the underlying mechanism remains unclear. We have recently characterized DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. We have now examined the effects of estrogen replacement on cardiac pathophysiology in ovariectomized female DS/obese (Ovx-DS/obese) rats. Animals subjected to ovariectomy at 7 weeks of age were implanted subcutaneously with a 60-day release pellet containing 0.5 mg of 17␤-estradiol (E 2 ) or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Lepr ϩ /Lepr ϩ or DS/lean rats) of DS/obese rats served as controls. Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 13 weeks of age. Ovx-DS/obese rats manifested hypertension at 7 weeks of age and thereafter and showed left ventricular (LV) fibrosis and diastolic dysfunction at 13 weeks. Treatment with E 2 attenuated hypertension in Ovx-DS/obese rats but had no effect on blood pressure in ovariectomized female DS/lean (Ovx-DS/lean) rats. E 2 treatment exacerbated LV fibrosis and diastolic dysfunction, as well as further increased cardiac oxidative stress and inflammation in Ovx-DS/obese rats, and it elicited similar effects in Ovx-DS/lean rats. E 2 reduced food intake, body weight, and visceral fat content in both Ovx-DS/obese and Ovx-DS/lean rats. E 2 treatment attenuated hypertension and obesity but exacerbated LV fibrosis and diastolic dysfunction in Ovx-DS/obese rats, with these latter effects being associated with increased cardiac oxidative stress and inflammation. (Hypertension. 2012;59:694-704.) • Online Data Supplement Key Words: metabolic syndrome Ⅲ estrogen Ⅲ hypertension Ⅲ myocardial fibrosis Ⅲ diastolic dysfunction Ⅲ oxidative stress Ⅲ inflammation M etabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus, and dyslipidemia, is associated with the development of visceral obesity. 1 MetS afflicts both men and women and increases the risk of heart disease in both sexes, although it appears to inflict a greater burden in women. The incidence of cardiovascular disease among women is low before menopause but steadily increases thereafter. 2 This increase is thought to result in part from the loss of endogenous estrogen and its associated cardioprotective effects. 3 A key issue faced by most postmenopausal women is the potential impact of estrogen replacement therapy on the prevalence of cardiovascular disease. Estrogen replacement in postmenopausal women has been associated with a reduced risk of cardiovascular disease. 4 However, the Heart and Estrogen/Progestin Replacement Study 5 and the Women's Health Initiative Study 6 do not support the notion that hormone replacement therapy protects the cardiovascular system but rather suggest the opposite vi...

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“…ER␣ and ER␤ are expressed in the endothelium (9) and smooth muscle (10) of blood vessels and in neonatal cardiomyocytes in culture, but only when estradiol is added to the culture medium (11). Some studies report that ER␤ cannot be detected in the adult heart (12), whereas in others ER␤ is abundant in the nucleus (13)(14)(15)(16), and in one study ER␤ was exclusively mitochondrial (17).…”

mentioning

confidence: 99%

Characterization of the ERβ ^– /–mouse heart

Förster

Kietz

Hultenby

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Although the heart responds to estrogen, it is not clear whether estrogen acts directly on heart muscle or indirectly by means of the vascular, immune, or nervous system. No role for estrogen receptor (ER) β in the heart has been established, but ERβ –/– mice are hypertensive, and as they age, their hearts become enlarged. Histological and ultrastructural analysis of the heart revealed a disarray of myocytes, a disruption of intercalated discs, an increase in the number and size of gap junctions, and a profound alteration in nuclear structure, concomitantly with a loss of expression of lamin A/C from the nuclear envelope. In the lungs of ERβ –/– mice, lamin A/C was located in the nuclear membrane, indicating that lamin A/C is not an ERβ-regulated gene. Immunohistochemical studies with ERβ antibodies failed to detect ERβ in the myocardium. We conclude that abnormalities in heart morphology in ERβ –/– mice are likely due to stress on the nuclear envelope as a result of the chronic sustained systolic and diastolic hypertension observed in ERβ –/– mice. Because neither ERα nor ERβ could be detected in heart muscle, the effects of estrogen on the myocardium seem to be indirect.

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Modulation of hypertensive heart disease by estrogen

Cited by 46 publications

References 17 publications

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z- Lepr ^fa /Lepr ^fa Rats as a New Animal Model of Metabolic Syndrome

Characterization of the ERβ ^– /–mouse heart

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Modulation of hypertensive heart disease by estrogen

Cited by 46 publications

References 17 publications

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z- Lepr fa /Lepr fa Rats as a New Animal Model of Metabolic Syndrome

Characterization of the ERβ – /–mouse heart

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Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z- Lepr ^fa /Lepr ^fa Rats as a New Animal Model of Metabolic Syndrome

Characterization of the ERβ ^– /–mouse heart