Upregulation of Myocardial Estrogen Receptors in Human Aortic Stenosis

Nordmeyer, Johannes; Eder, Sarah; Mahmoodzadeh, Shokoufeh; Martus, Peter; Fielitz, Jens; Bass, Jan; Bethke, Nicole; Zurbrügg, H. R.; Pregla, Reinhard; Hetzer, Roland; Regitz‐Zagrosek, Vera

doi:10.1161/01.cir.0000147610.41984.e8

Cited by 118 publications

(93 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…23 An upregulation of ERa at both mRNA and protein level was associated with human aortic stenosis and with the end-stage human heart failure due to dilated cardiomyopathy. 21 In both cases, ERa was expressed at a comparable concentration in women and in men, and the increase in ERa occurred in both. 22 We demonstrated that the expression of ERs in human atrial slices was not changed following 24 h exposure to E2 treatment.…”

Section: Discussionmentioning

confidence: 84%

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Bukowska

Spiller²,

Wolke

et al. 2017

Exp Biol Med (Maywood)

175

183

View full text Add to dashboard Cite

The present study demonstrates that estrogen affects the human atrial myocardium and mediates protective actions through estrogen receptors-(ER) dependent signaling. Estrogen substantially modulates the local RAS via downregulation of ACE and simultaneous upregulation of ACE2, AT2R and MAS expression levels. This is indicative of a shift of the classical RAS/ACE axis to the alternative, protective RAS/ACE2 axis. In support of this view, estrogen attenuated the expression of RAS-associated downstream effectors, LOX-1, and ICAM-1. A specific antagonist of ERa reversed the anti-inflammatory and anti-oxidative effects of estrogen in paced and nonpaced atrial tissue slices. In summary, our data demonstrate the existence of protective effects of estrogen in atrial tissue from elderly men which are at least in part, mediated by the regulation of local RAS homeostasis. AbstractData from animal experiments and clinical investigations suggest that components of the renin-angiotensin system are markedly affected by sex hormones. However, whether estrogen affects human atrial myocardium has not been investigated yet. In this study, we determined the effects of estrogen on key components of atrial renin-angiotensin system: angiotensin-converting enzyme, responsible for generation of angiotensin II and angiotensin-converting enzyme 2, counteracting majority of AngII effects, and different renin-angiotensin system receptors, AT1R, AT2R, and MAS. First, the expression levels of estrogen receptors mRNA were determined in right atrial appendages obtained from patients undergoing heart surgery. The amounts of estrogen receptor a and estrogen receptor b mRNA were similar between women (n ¼ 14) and men (n ¼ 10). Atrial tissue slices (350 mm) were prepared from male donors which were exposed to estrogen (1-100 nM; n ¼ 21) or stimulated at 4 Hz for 24 h in the presence or absence of 100 nM estrogen (n ¼ 16), respectively. The administration of estrogen did not change mRNA levels of estrogen receptors, but activated MAP kinases, Erk1/2. Furthermore, estrogen increased the amounts of angiotensin-converting enzyme 2-mRNA (1.89 AE 0.23; P < 0.05) but reduced that of angiotensin-converting enzyme-mRNA (0.78 AE 0.07, P < 0.05). In addition, the transcript levels of AT2R and MAS were upregulated by estrogen. Pacing of tissue slices significantly increased the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at both the mRNA and protein level. During pacing, administration of estrogen substantially lowered the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at the transcript (0.92 AE 0.21 vs. 2.12 AE 0.27 at 4 Hz) and protein level (0.94 AE 0.20 vs. 2.14 AE 0.3 at 4 Hz). Moreover, estrogen elicited anti-inflammatory and anti-oxidative effects on renin-angiotensin system-associated downstream effectors such as pro-oxidative LOX-1 and pro-inflammatory ICAM-1. An antagonist of estrogen receptor a reversed these anti-inflammatory and anti-oxidative effects of estrogen significantly. Overall, our results demo...

show abstract

Section: Discussionmentioning

confidence: 84%

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Bukowska

Spiller²,

Wolke

et al. 2017

Exp Biol Med (Maywood)

175

183

View full text Add to dashboard Cite

show abstract

“…Testosterone circulates at concentrations that are an order of magnitude greater than those of E 2 in the blood of postmenopausal women (Simpson 2002). In addition, androgen receptors are expressed in female hearts (Nordmeyer et al 2004, Lizotte et al 2009). An implication of the above is that androgens have an important role in the higher risk of CVD in postmenopausal women.…”

Section: Discussionmentioning

confidence: 99%

Testosterone enhances estradiol's cardioprotection in ovariectomized rats

Liú

Gao²,

Kang

et al. 2011

Journal of Endocrinology

View full text Add to dashboard Cite

After menopause, the development of cardiovascular disease (CVD) is due not only to estrogen decline but also to androgen decline. This study examined the effects of either estradiol (E 2 ) or testosterone replacement alone or E 2 -testosterone combination on isolated myocytes in ovariectomized (Ovx) rats subjected to ischemia/reperfusion (I/R). Furthermore, we determined whether the effects are associated with b 2 -adrenoceptor (b 2 -AR). Five groups of adult female Sprague-Dawley rats were used: Sham operation (Sham) rats, bilateral Ovx rats, Ovx rats with E 2 40 mg/kg per day (OvxCE), Ovx rats with testosterone 150 mg/kg per day (OvxCT), and Ovx rats with E 2 40 mg/kg per dayC testosterone 150 mg/kg per day (OvxCE/T). We determined the lactate dehydrogenase (LDH) release, percentage of rod-shaped cells and apoptosis of ventricular myocytes from rats of all groups subjected to I/R. Then, we determined the above indices and contractile function with or without a selective b 2 -AR antagonist ICI 118 551. We also determined the expression of b 2 -AR. Our data show that either E 2 or testosterone replacement alone or E 2 and testosterone in combination decreased the LDH release, increased the percentage of rod-shaped cells, reduced apoptotic cells (%), and combination treatment appeared to be more effective than either E 2 or testosterone replacement alone. ICI 118 551 abolished the effects of the three. Combination supplementation also enhanced the expression of b 2 -AR. We concluded that in Ovx rats, testosterone enhances E 2 's cardioprotection, while E 2 and testosterone in combination was more effective and the protective effects may be associated with b 2 -AR. The study highlights the potential therapeutic application for CVD in postmenopausal women.

show abstract

“…29,30 In contrast to previous studies, which failed to detect measurable amounts of ER␣ and ER␤ protein in the mouse heart, several independent studies reported on robust cardiac expression levels of both ER subtypes in rats and humans. 10,31,32 However, cardiac expression levels of ER␣ and ER␤ may not only vary between different species but also among young and senescent SHRs. Therefore, it is interesting to note that cardiac ER␣ expression was significantly lower in sham-operated and ovariectomized aged rats, whereas ER␤ was detected at comparable amounts in the heart of young and senescent rats.…”

Section: Discussionmentioning

confidence: 99%

Aging Reduces the Efficacy of Estrogen Substitution to Attenuate Cardiac Hypertrophy in Female Spontaneously Hypertensive Rats

Jazbutyte

Kruchten

et al. 2006

Hypertension

View full text Add to dashboard Cite

Abstract-Clinical trials failed to show a beneficial effect of postmenopausal hormone replacement therapy, whereas experimental studies in young animals reported a protective function of estrogen replacement in cardiovascular disease. Because these diverging results could in part be explained by aging effects, we compared the efficacy of estrogen substitution to modulate cardiac hypertrophy and cardiac gene expression among young (age 3 months) and senescent (age 24 months) spontaneously hypertensive rats (SHRs), which were sham operated or ovariectomized and injected with placebo or identical doses of 17␤-estradiol (E2; 2 g/kg body weight per day) for 6 weeks (nϭ10/group). Blood pressure was comparable among sham-operated senescent and young SHRs and not altered by ovariectomy or E2 treatment among young or among senescent rats. Estrogen substitution inhibited uterus atrophy and gain of body weight in young and senescent ovariectomized SHRs, but cardiac hypertrophy was attenuated only in young rats. Cardiac estrogen receptor-␣ expression was lower in intact and in ovariectomized senescent compared with young SHRs and increased with estradiol substitution in aged rats. Plasma estradiol and estrone levels were lower not only in sham-operated but surprisingly also in E2-substituted senescent SHRs and associated with a reduction of hepatic 17␤-hydroxysteroid dehydrogenase type 1 enzyme activity, which converts weak (ie, estrone) into potent estrogens, such as E2. Aging attenuates the antihypertrophic effect of estradiol in female SHRs and is associated with profound alterations in cardiac estrogen receptor-␣ expression and estradiol metabolism. These observations contribute to explain the lower efficiency of estrogen substitution in senescent SHRs. (Hypertension. 2006;48:579-586.)

show abstract

Upregulation of Myocardial Estrogen Receptors in Human Aortic Stenosis

Cited by 118 publications

References 24 publications

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

Testosterone enhances estradiol's cardioprotection in ovariectomized rats

Aging Reduces the Efficacy of Estrogen Substitution to Attenuate Cardiac Hypertrophy in Female Spontaneously Hypertensive Rats

Contact Info

Product

Resources

About