Estrogen receptor profiling and activity in cardiac myocytes

Pugach, Emily K.; Blenck, Christa L.; Dragavon, Joseph; Langer, Shelby L.; Leinwand, Leslie A.

doi:10.1016/j.mce.2016.05.004

Cited by 59 publications

(52 citation statements)

References 65 publications

(107 reference statements)

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“…Additionally, we previously described that ER transcript expression is quite low, restricted to ERα and not sexually dimorphic in cardiac myocytes, 32 prompting our interest in understanding what other pathways are involved in mediating the functional sex differences we observed at baseline. However, differences in hormone signaling between the sexes could be a source of variation leading to the genetic and functional differences in the myocytes.…”

Section: Discussionmentioning

confidence: 76%

Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex

Trexler

Odell

Jeong

et al. 2017

Circ Cardiovasc Genet

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Background Although cardiovascular disease (CVD) is the primary killer of women in the U.S., women and female animals have traditionally been omitted from research studies. In reports that do include both sexes, significant sexual dimorphisms have been demonstrated in development, presentation and outcome of CVD. However, there is little understanding of the mechanisms underlying these observations. A more thorough understanding of sex-specific cardiovascular differences both at baseline and in disease is required to effectively consider and treat all CVD patients. Methods & Results We analyzed contractility in the whole rat heart, adult rat ventricular myocytes (ARVMs) and myofibrils from both sexes of rats and observed functional sex differences at all levels. Hearts and ARVMs from female rats displayed greater fractional shortening than males, and female ARVMs and myofibrils took longer to relax. To define factors underlying these functional differences, we performed an RNA-sequencing experiment on ARVMs from male and female rats and identified ~600 genes were expressed in a sexually dimorphic manner. Further analysis revealed sex-specific enrichment of signaling pathways and key regulators. At the protein level, female ARVMs exhibited higher PKA activity, consistent with pathway enrichment identified through RNA-seq. Additionally, activating the PKA pathway diminished the contractile sexual dimorphisms previously observed. Conclusions These data support the notion that sex-specific gene expression differences at baseline influence cardiac function, particularly through the PKA pathway, and could potentially be responsible for differences in CVD presentation and outcomes.

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Section: Discussionmentioning

confidence: 76%

Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex

Trexler

Odell

Jeong

et al. 2017

Circ Cardiovasc Genet

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“…A recent study, which reported the presence of ERα and a lack of ERβ expression in cardiomyocytes [36] prompted us to initially focus on ERα. This was accomplished by generating a tamoxifen-inducible cardiomyocyte-specific ER α knock out mouse (cs-ERαKO), as detailed in the Material and Method section.…”

Section: Resultsmentioning

confidence: 99%

Non-nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia-reperfusion injury in mice

Menazza

Sun

Appachi

et al. 2017

Journal of Molecular and Cellular Cardiology

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Steroid hormone receptors including estrogen receptors (ER) classically function as ligand-regulated transcription factors. However, estrogens also elicit cellular effects through binding to extra-nuclear ER (ERα, ERβ, and G protein-coupled ER or GPER) that are coupled to kinases. How extra-nuclear ER actions impact cardiac ischemia-reperfusion (I/R) injury is unknown. We treated ovariectomized wild-type female mice with estradiol (E2) or an estrogen-dendrimer conjugate (EDC), which selectively activates extra-nuclear ER, or vehicle interventions for two weeks. I/R injury was then evaluated in isolated Langendorff perfused hearts. Two weeks of treatment with E2 significantly decreased infarct size and improved post-ischemic contractile function. Similarly, EDC treatment significantly decreased infarct size and increased post-ischemic functional recovery compared to vehicle-treated hearts. EDC also caused an increase in myocardial protein S-nitrosylation, consistent with previous studies showing a role for this post-translational modification in cardioprotection. In further support of a role for S-nitrosylation, inhibition of nitric oxide synthase, but not soluble guanylyl cyclase blocks the EDC mediated protection. The administration of ICI182,780, which is an agonist of G-protein coupled estrogen receptor (GPER) and an antagonist of ERα and ERβ, did not result in protection; however, ICI182,780 significantly blocked EDC-mediated cardioprotection, indicating participation of ERα and/or ERβ. In studies determining the specific ER subtype and cellular target involved, EDC decreased infarct size and improved functional recovery in mice lacking ERα in cardiomyocytes. In contrast, protection was lost in mice deficient in endothelial cell ERα. Thus, extra-nuclear ERα activation in endothelium reduces cardiac I/R injury in mice, and this likely entails increased protein S-nitrosylation. Since EDC does not stimulate uterine growth, in the clinical setting EDC-like compounds may provide myocardial protection without undesired uterotrophic and cancer-promoting effects.

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“…5,21,22 Our results showed that the expression level of ERa mRNA and ERb mRNA was similar between women and men and this is consistent with other studies describing no sex differences in the expression of ERs in human 22 and in animal heart. 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.…”

Section: Discussionmentioning

confidence: 99%

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

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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...

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Estrogen receptor profiling and activity in cardiac myocytes

Cited by 59 publications

References 65 publications

Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex

Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex

Non-nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia-reperfusion injury in mice

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

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