双酚 A 和 17β-雌二醇通过改变钙处理促进女性心脏心律失常。
Bisphenol A and 17β-estradiol promote arrhythmia in the female heart via alteration of calcium handling.
机构信息
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
出版信息
PLoS One. 2011;6(9):e25455. doi: 10.1371/journal.pone.0025455. Epub 2011 Sep 27.
BACKGROUND
There is wide-spread human exposure to bisphenol A (BPA), a ubiquitous estrogenic endocrine disruptor that has been implicated as having potentially harmful effects on human heart health. Higher urine BPA concentrations have been shown to be associated with cardiovascular diseases in humans. However, neither the nature nor the mechanism(s) of BPA action on the heart are understood.
METHODOLOGY/PRINCIPAL FINDINGS: The rapid (<7 min) effects of BPA and 17β-estradiol (E2) in the heart and ventricular myocytes from rodents were investigated in the present study. In isolated ventricular myocytes from young adult females, but not males, physiological concentrations of BPA or E2 (10⁻⁹ M) rapidly induced arrhythmogenic triggered activities. The effects of BPA were particularly pronounced when combined with estradiol. Under conditions of catecholamine stimulation, E2 and BPA promoted ventricular arrhythmias in female, but not male, hearts. The cellular mechanism of the female-specific pro-arrhythmic effects of BPA and E2 were investigated. Exposure to E2 and/or BPA rapidly altered myocyte Ca²⁺ handling; in particular, estrogens markedly increased sarcoplasmic reticulum (SR) Ca²⁺ leak, and increased SR Ca²⁺ load. Ryanodine (10⁻⁷ M) inhibition of SR Ca²⁺ leak suppressed estrogen-induced triggered activities. The rapid response of female myocytes to estrogens was abolished in an estrogen receptor (ER) β knockout mouse model.
CONCLUSIONS/SIGNIFICANCE: Physiologically-relevant concentrations of BPA and E2 promote arrhythmias in a female-specific manner in rat hearts; the pro-arrhythmic actions of estrogens are mediated by ERβ-signaling through alterations of myocyte Ca²⁺ handling, particularly increases in SR Ca²⁺ leak. Our study provides the first experimental evidence suggesting that exposure to estrogenic endocrine disrupting chemicals and the unique sensitivity of female hearts to estrogens may play a role in arrhythmogenesis in the female heart.
背景
双酚 A（BPA）广泛存在于人类环境中，是一种普遍存在的雌激素内分泌干扰物，被认为对人类心脏健康可能有害。较高的尿液 BPA 浓度与人类心血管疾病有关。然而，BPA 对心脏的作用的性质和机制尚不清楚。
方法/主要发现：本研究调查了 BPA 和 17β-雌二醇（E2）在心脏和啮齿动物心室肌细胞中的快速（<7 分钟）作用。在年轻成年雌性而非雄性的分离心室肌细胞中，生理浓度的 BPA 或 E2（10⁻⁹ M）可迅速诱导心律失常性触发活动。当与雌二醇结合时，BPA 的作用尤为明显。在儿茶酚胺刺激下，E2 和 BPA 促进雌性而非雄性心脏的室性心律失常。研究了 BPA 和 E2 对雌性特有的致心律失常作用的细胞机制。暴露于 E2 和/或 BPA 可迅速改变肌细胞 Ca²⁺处理；特别是，雌激素显著增加肌浆网（SR）Ca²⁺渗漏，并增加 SR Ca²⁺负荷。肌浆网 Ca²⁺渗漏的 Ryanodine（10⁻⁷ M）抑制抑制了雌激素诱导的触发活动。雌激素受体（ER）β敲除小鼠模型中雌性肌细胞对雌激素的快速反应被消除。
结论/意义：生理相关浓度的 BPA 和 E2 以雌性特异性方式促进大鼠心脏的心律失常；雌激素的致心律失常作用是通过 ERβ 信号转导介导的，通过改变肌细胞 Ca²⁺处理，特别是增加肌浆网 Ca²⁺渗漏。我们的研究首次提供了实验证据，表明暴露于雌激素内分泌干扰化学物质和雌性心脏对雌激素的独特敏感性可能在女性心脏心律失常发生中起作用。
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