Genetic Background Defines the Regulation of Postnatal Cardiac Growth by 17β-Estradiol Through a β-Catenin Mechanism
Genetic Background Defines the Regulation of Postnatal Cardiac Growth by 17β-Estradiol Through a β-Catenin Mechanism
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DOI：
10.1210/en.2013-2180
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发表时间：
2014-07-01
期刊：
影响因子：
4.8
通讯作者：
Regitz-Zagrosek, Vera
中科院分区：
文献类型：
--
作者：
Kararigas, Georgios;Ba Tiep Nguyen;Regitz-Zagrosek, Vera
雌激素调节健康和疾病中的几个生物过程。具体来说，雌激素在患病心脏发挥抗肥厚作用。然而，它在健康心脏中的作用仍然难以捉摸。我们最初的目的是确定17 β -雌二醇（E2）对健康小鼠心脏形态和整体基因表达的影响。切除2月龄C57BL/6J小鼠卵巢，用E2或代药治疗3个月。我们报道E2诱导健康C57BL/6J小鼠心脏的生理性肥厚生长，其特征是核β -连环蛋白的增加。假设β -catenin介导E2的这些作用，我们采用了心脏β -catenin缺失模型。我们令人惊讶的发现是E2在C57BL/6N背景下的野生型幼崽中有相反的作用。值得注意的是，E2对β -连环蛋白缺失小鼠的心脏没有显著影响。我们进一步证明，C57BL/6J小鼠的糖原合成酶激酶3 β (GSK3 β)磷酸化和内体标记物的e2依赖性增加，而C57BL/6N小鼠则没有。总之，这些发现表明e2驱动的GSK3 β抑制和随后的β -连环蛋白激活在C57BL/6J小鼠中，而在C57BL/6N小鼠中发生相反的情况。综上所述，E2对具有不同遗传背景的小鼠的出生后心脏生长具有不同的影响，可以调节GSK3 β / β -连环蛋白级联的成员。
Estrogen regulates several biological processes in health and disease. Specifically, estrogen exerts antihypertrophic effects in the diseased heart. However, its role in the healthy heart remains elusive. Our initial aim was to identify the effects of 17 beta-estradiol (E2) on cardiac morphology and global gene expression in the healthy mouse heart. Two-month-old C57BL/6J mice were ovariectomized and treated with E2 or vehicle for 3 months. We report that E2 induced physiological hypertrophic growth in the healthy C57BL/6J mouse heart characterized by an increase in nuclear beta-catenin. Hypothesizing that beta-catenin mediates these effects of E2, we employed a model of cardiac beta-catenin deletion. Our surprising finding is that E2 had the opposite effects in wild-type littermates, which were actually on the C57BL/6N background. Notably, E2 exerted no significant effect in hearts of mice with depleted beta-catenin. We further demonstrate an E2-dependent increase in glycogen synthase kinase 3 beta (GSK3 beta) phosphorylation and endosomal markers in C57BL/6J but not C57BL/6N mice. Together, these findings indicate an E2-driven inhibition of GSK3 beta and consequent activation of beta-catenin in C57BL/6J mice, whereas the opposite occurs in C57BL/6N mice. In conclusion, E2 exerts divergent effects on postnatal cardiac growth in mice with distinct genetic backgrounds modulating members of the GSK3 beta/beta-catenin cascade.