Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation.
Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation.
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雌激素通过雌激素受体依赖性途径增加钙调神经素降解的途径。
DOI：
10.1161/circresaha.108.190397
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发表时间：
2009-01-30
影响因子：
20.1
通讯作者：
Patten RD
中科院分区：
文献类型：
--
作者：
Donaldson C;Eder S;Baker C;Aronovitz MJ;Weiss AD;Hall-Porter M;Wang F;Ackerman A;Karas RH;Molkentin JD;Patten RD
左心室（LV）肥大通常是慢性高血压的反应，是心力衰竭和死亡的重要危险因素。丝氨酸-苏氨酸磷酸酶，钙调神经磷酸酶（CnA），在病理性肥大的发展中起着关键作用。先前在小鼠模型中的实验研究表明，雌激素限制压力超负荷诱导的肥大;我们的目的是进一步探索这种雌激素效应的机制。用安慰剂或17β-雌二醇（E2）处理野生型卵巢切除雌性小鼠，然后进行横向主动脉缩窄（TAC）以诱导压力超负荷。两周后，小鼠接受生理评估、立即组织采集或心肌细胞分散。E2替代限制了TAC诱导的LV和心肌细胞肥大，同时减轻了LV收缩功能和收缩力的恶化。这些E2效应与CnA丰度降低相关。CnA的主要下游靶标是转录因子的活化T细胞核因子（NFAT）家族。在转基因小鼠表达NFAT激活的启动子荧光素酶报告基因，E2限制TAC诱导的NFAT激活。此外，在CnA基因敲除小鼠中不存在E2对LV肥大的抑制作用，这支持CnA是E2介导的抑制的重要靶点。在培养的大鼠心肌细胞中，E2抑制激动剂诱导的肥大，同时也降低CnA丰度和NFAT激活。激动剂的刺激也减少CnA泛素化和降解，防止E2的雌激素的体外作用被逆转的ER拮抗剂。这些数据支持E2通过增加CnA降解的ER依赖性机制减少压力超负荷诱导的肥大，揭示了E2和ER调节病理性LV和心肌细胞生长的新机制。
Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase, calcineurin (CnA), plays a critical role in the development of pathologic hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild type, ovariectomized female mice were treated with placebo or 17β-estradiol (E2), followed by transverse aortic constriction (TAC) to induce pressure overload. At two weeks, mice underwent physiologic evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter-luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice supporting that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an ER antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathologic LV and cardiomyocyte growth.