Sugishita K, Li F, Su Z, Barry W H
Division of Cardiology, University of Utah Health Sciences Center, 50 N Medical Drive, Salt Lake City, UT 84132, USA.
J Mol Cell Cardiol. 2003 Mar;35(3):331-6. doi: 10.1016/s0022-2828(03)00017-8.
We previously reported that 17beta-estradiol (betaE2) inhibits the rise in Ca(2+) and Na(+) during metabolic inhibition (MI) in mouse cardiomyocytes, but the mechanism has not yet been clarified. Estrogen has been reported to have anti-oxidant properties. We, therefore, have investigated whether interaction with the estrogen receptor (ER) is involved, or whether estrogen reduces free-radical-induced impairment of Na(+)-K(+) ATPase in cardiac myocytes, and whether this effect reduces Ca(2+) rise. Male mouse ventricular myocytes were studied. Flow cytometry was used with fluo-3 for Ca(2+) measurement. Dead cells were excluded from analysis by propidium iodide fluorescence. betaE2 reduced the increase in Ca(2+) during MI even in the presence of the ER blocker tamoxifen. A similar effect on Ca(2+) was produced by its non-estrogenic isomer, betaE2-estradiol. Other hormones (estrone and estriol) with a phenolic structure also inhibited Ca(2+) overload during MI, but testosterone without the structure did not. The betaE2 effect was attenuated by inhibition of Na(+)-Ca(2+) exchanger (KB-R7943) or Na(+)-K(+) ATPase (low K(+) or ouabain), but not by block of L-type Ca(2+) channel (nifedipine). Tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid), a superoxide scavenger, decreased the rise in Ca(2+) and abolished the betaE2 effect during MI. We conclude that the acute cardioprotective effect of estrogen during MI may be mediated by an ER-independent anti-oxidant action, which results in improved function of Na(+)-K(+) ATPase.
我们之前报道过，17β-雌二醇（βE2）可抑制小鼠心肌细胞代谢抑制（MI）期间细胞内钙离子浓度（Ca(2+)）和钠离子浓度（Na(+)）的升高，但其机制尚未阐明。据报道，雌激素具有抗氧化特性。因此，我们研究了其是否涉及与雌激素受体（ER）的相互作用，雌激素是否能减少自由基诱导的心肌细胞钠钾ATP酶损伤，以及这种作用是否能降低Ca(2+)的升高。我们对雄性小鼠心室肌细胞进行了研究。使用流式细胞术结合荧光素-3来测量Ca(2+)。通过碘化丙啶荧光排除死细胞进行分析。即使存在ER阻滞剂他莫昔芬，βE2仍能降低MI期间Ca(2+)的升高。其非雌激素异构体βE2-雌二醇对Ca(2+)产生了类似的作用。其他具有酚类结构的激素（雌酮和雌三醇）也能抑制MI期间的钙超载，但没有该结构的睾酮则不能。抑制钠钙交换体（KB-R7943）或钠钾ATP酶（低钾或哇巴因）可减弱βE2的作用，但阻断L型钙通道（硝苯地平）则无此作用。超氧化物清除剂替诺（4,5-二羟基-1,3-苯二磺酸）可降低Ca(2+)的升高，并消除MI期间βE2的作用。我们得出结论，MI期间雌激素的急性心脏保护作用可能由不依赖ER的抗氧化作用介导，这导致钠钾ATP酶功能得到改善。
