Donaldson Cameron, Eder Sarah, Baker Corey, Aronovitz Mark J, Weiss Alexandra Dabreo, Hall-Porter Monica, Wang Feng, Ackerman Adam, Karas Richard H, Molkentin Jeffery D, Patten Richard D
Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA.
Circ Res. 2009 Jan 30;104(2):265-75, 11p following 275. doi: 10.1161/CIRCRESAHA.108.190397. Epub 2008 Dec 12.
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 (Cn)A plays a critical role in the development of pathological 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 17beta-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 weeks, mice underwent physiological 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 the notion 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 estrogen receptor (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 pathological LV and cardiomyocyte growth.
左心室（LV）肥厚通常是对慢性高血压的反应而发生的，并且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（Cn）A在病理性肥厚的发展中起关键作用。先前在小鼠模型中的实验研究表明，雌激素可限制压力超负荷诱导的肥厚；我们的目的是进一步探索这种雌激素作用的潜在机制。对野生型、卵巢切除的雌性小鼠给予安慰剂或17β - 雌二醇（E2），随后进行主动脉缩窄（TAC），以诱导压力超负荷。在2周时，对小鼠进行生理评估、立即采集组织或分离心肌细胞。E2替代可限制TAC诱导的左心室和心肌细胞肥厚，同时减轻左心室收缩功能和收缩性的恶化。这些E2效应与CnA丰度降低有关。CnA的主要下游靶点是活化T细胞的核因子（NFAT）转录因子家族。在表达NFAT激活启动子/荧光素酶报告基因的转基因小鼠中，E2限制了TAC诱导的NFAT激活。此外，在CnA基因敲除小鼠中，E2对左心室肥厚的抑制作用不存在，这支持了CnA是E2介导抑制的重要靶点这一观点。在培养的大鼠心肌细胞中，E2抑制激动剂诱导的肥厚，同时也降低CnA丰度和NFAT激活。激动剂刺激还减少了CnA的泛素化和降解，而E2可阻止这种情况；雌激素的所有体外效应均被雌激素受体（ER）拮抗剂逆转。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厚，揭示了E2和ER调节病理性左心室和心肌细胞生长的新机制。
