Rapid Changes in Cardiac Myofilament Function following the Acute Activation of Estrogen Receptor-Alpha

Kulpa, Justyna; Chinnappareddy, Nirmala; Pyle, W. Glen

doi:10.1371/journal.pone.0041076

Cited by 22 publications

(17 citation statements)

References 32 publications

(43 reference statements)

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“…Time to peak and times from peak to 25%, 50% and 75% Ca 2+ transient decay were dose-dependently increased (Figure 5H and Table S3), reflecting sarcomere length measurements. A potential mechanism for slow Ca 2+ transient decay is acute ER signaling through PKA to alter the phosphorylation status of cTnI [27,29,33]. To test this, cardiac myocytes were treated with Ral +/- isoproterenol to determine whether Ral causes dephosphorylation of cTnI.…”

Section: Resultsmentioning

confidence: 99%

“…Acute, non-genomic effects of Tam administration have thus far not been considered as a contributor to Tam-induced dilated cardiomyopathy in Tg(αMHC-MerCreMer) mice. PKA is implicated as a non-genomic signaling target of ERs with 17β-estradiol, causing decreased phosphorylation of PKA target proteins with subsequent alterations in contraction and SR Ca 2+ release and reuptake [27–29]. It is currently unknown whether acute ER signaling through Tam has direct effects on cardiac myocyte function.…”

Section: Introductionmentioning

confidence: 99%

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Direct, Differential Effects of Tamoxifen, 4-Hydroxytamoxifen, and Raloxifene on Cardiac Myocyte Contractility and Calcium Handling

2013

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Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. High Tam doses have been used for treatment of gliomas and cancers with multiple drug resistance, but long QT Syndrome is a side effect. Tam is also used experimentally in mice for inducible gene knockout in numerous tissues, including heart; however, the potential direct effects of Tam on cardiac myocyte mechanical function are not known. The goal of this study was to determine the direct, acute effects of Tam, its active metabolite 4-hydroxytamoxifen (4OHT), and related drug raloxifene (Ral) on isolated rat cardiac myocyte mechanical function and calcium handling. Tam decreased contraction amplitude, slowed relaxation, and decreased Ca2+ transient amplitude. Effects were primarily observed at 5 and 10 μM Tam, which is relevant for high dose Tam treatment in cancer patients as well as Tam-mediated gene excision in mice. Myocytes treated with 4OHT responded similarly to Tam-treated cells with regard to both contractility and calcium handling, suggesting an estrogen-receptor independent mechanism is responsible for the effects. In contrast, Ral increased contraction and Ca2+ transient amplitudes. At 10 μM, all drugs had a time-dependent effect to abolish cellular contraction. In conclusion, Tam, 4OHT, and Ral adversely and differentially alter cardiac myocyte contractility and Ca2+ handling. These findings have important implications for understanding the Tam-induced cardiomyopathy in gene excision studies and may be important for understanding effects on cardiac performance in patients undergoing high-dose Tam therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Direct, Differential Effects of Tamoxifen, 4-Hydroxytamoxifen, and Raloxifene on Cardiac Myocyte Contractility and Calcium Handling

2013

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“…For example, in mice, the effects of estrogens mediated by ERα can improve vascular function and reduce atherosclerosis [110]. Some studies also showed that estrogen can prevent cardiac fibrosis by blocking the fibroblast to myofibroblast transition via interactions with ERβ [111].…”

Section: Estrogen and Ers In Age–related Diseasesmentioning

confidence: 99%

Estrogen synthesis and signaling pathways during aging: from periphery to brain

Cui

Shen

2013

Trends in Molecular Medicine

597

426

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Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissue as liver, heart, muscle, bone and brain. The tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. Here, we will focus on tissue and cell-specific estrogen synthesis and estrogen receptor signaling. This review will include three parts: (I) tissue and cell-specific estrogen synthesis and metabolism, (II) tissue and cell-specific distribution of estrogen receptors and signaling and (III) tissue-specific estrogen function and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease and Parkinson disease. This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases.

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“…Acute application of high concentrations (10 to 30 μM) of 17β-estradiol also reduces the amplitudes of Ca 2+ transients and contractions in isolated ventricular myocytes [57, 110]. Interestingly, stimulation of oestrogen receptor α with PPT (4,49,499-(4-propyl-[1 H ]-pyrazole-1,3,5-triyl) trisphenol; 100 nM) has been shown to decrease myofilament Ca 2+ sensitivity [64]. There is also evidence that oestrogen can acutely modify electrophysiological properties of the heart.…”

Section: The Impact Of Sex Steroid Hormones On Cardiac Ec Coupling Mementioning

confidence: 99%

Sex differences in mechanisms of cardiac excitation–contraction coupling

Parks

Howlett

2013

Pflugers Arch - Eur J Physiol

116

101

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The incidence and expression of cardiovascular diseases differs between the sexes. This is not surprising, as cardiac physiology differs between men and women. Clinical and basic science investigations have shown important sex differences in cardiac structure and function. The pervasiveness of sex differences suggests that such differences must be fundamental, likely operating at a cellular level. Indeed, studies have shown that isolated ventricular myocytes from female animals have smaller and slower contractions and underlying calcium transients compared to males. Recent evidence suggests that this arises from sex differences in components of the cardiac excitation–contraction coupling pathway, the sequence of events linking myocyte depolarization to calcium release from the sarcoplasmic reticulum and subsequent contraction. The concept that sex hormones may regulate intracellular calcium at the level of the cardiomyocyte is important, as levels of these hormones decline in both men and women as the incidence of cardiovascular disease rises. This review focuses on the impact of sex on cardiac contraction, in particular at the cellular level, and highlights specific components of the excitation–contraction coupling pathway that differ between the sexes. Understanding sex hormone regulation of calcium homeostasis in the heart may reveal new avenues for therapeutic strategies to treat cardiac dysfunction and cardiovascular diseases.

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Rapid Changes in Cardiac Myofilament Function following the Acute Activation of Estrogen Receptor-Alpha

Cited by 22 publications

References 32 publications

Direct, Differential Effects of Tamoxifen, 4-Hydroxytamoxifen, and Raloxifene on Cardiac Myocyte Contractility and Calcium Handling

Direct, Differential Effects of Tamoxifen, 4-Hydroxytamoxifen, and Raloxifene on Cardiac Myocyte Contractility and Calcium Handling

Estrogen synthesis and signaling pathways during aging: from periphery to brain

Sex differences in mechanisms of cardiac excitation–contraction coupling

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