Estrogen inhibits cardiac hypertrophy:: Role of estrogen receptor-β to inhibit calcineurin
Estrogen inhibits cardiac hypertrophy:: Role of estrogen receptor-β to inhibit calcineurin
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DOI：
10.1210/en.2008-0133
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Levin, Ellis R.
中科院分区：
文献类型：
--
作者：
Pedram, Ali;Razandi, Mahnaz;Levin, Ellis R.
据报道，在雌性啮齿动物模型和人类中，雌激素可以防止心肌肥大的发生。然而，性激素的作用机制还不完全清楚。我们在体内测定了17β-雌二醇(E_2)抑制血管紧张素II(AngII)诱导的心肌肥大的细胞效应。在雌性小鼠体内注射血管紧张素两周后，其左心室显著肥大，而卵巢切除导致的卵巢类固醇激素的丢失加剧了这种肥大。给予雌二醇(0.1 mg/21d缓释片)可逆转51%的肥厚。E2的作用主要是通过雌激素受体(ER)β-亚型介导的，因为在ERβ缺失的小鼠中，E2几乎没有作用，但在野生型或ERβ缺失的小鼠中，E2对血管紧张素转换酶诱导的肥大有类似的抑制作用。血管紧张素转换酶诱导肌球蛋白重链的产生从α转换为β，但这一转换可被E2通过ERβ抑制。E_2可通过β受体抑制血管紧张素Ⅱ诱导的ERK激活。雌二醇刺激脑利钠多肽蛋白的表达，并实质上阻止血管紧张素转换酶诱导的心肌间质纤维化(胶原沉积)。重要的是，E_2抑制由血管紧张素Ⅱ刺激的钙调神经磷酸酶活性，这与E_2刺激钙调神经磷酸酶相互作用蛋白(MCIP)1基因和蛋白的表达有关。E2主要通过ERβ发挥作用，减轻血管紧张素转换酶II产生的重要信号，使雌性小鼠心肌肥大和纤维化。
Estrogen has been reported to prevent development of cardiac hypertrophy in female rodent models and in humans. However, the mechanisms of sex steroid action are incompletely understood. We determined the cellular effects by which 17 beta-estradiol (E2) inhibits angiotensin II (AngII)-induced cardiac hypertrophy in vivo. Two weeks of angiotensin infusion in female mice resulted in marked hypertrophy of the left ventricle, exacerbated by the loss of ovarian steroid hormones from oophorectomy. Hypertrophy was 51% reversed by the administration of E2 (insertion of 0.1 mg/21-d-release tablets). The effects of E2 were mainly mediated by the estrogen receptor (ER) beta-isoform, because E2 had little effect in ER beta-null mice but comparably inhibited AngII-induced hypertrophy in wild-type or ER beta-null mice. AngII induced a switch of myosin heavy chain production from alpha to beta, but this was inhibited by E2 via ER beta. AngII-induced ERK activation was also inhibited by E2 through the beta-receptor. E2 stimulated brain natriuretic peptide protein expression and substantially prevented ventricular interstitial cardiac fibrosis (collagen deposition) as induced by AngII. Importantly, E2 inhibited calcineurin activity that was stimulated by AngII, related to E2 stimulating the modulatory calcineurin-interacting protein (MCIP) 1 gene and protein expression. E2 acting mainly through ER beta mitigates the important signaling by AngII that produces cardiac hypertrophy and fibrosis in female mice.