雌激素受体β维持 KLF15 的表达，以防止雌性啮齿动物心肌细胞肥大。
Estrogen receptor beta maintains expression of KLF15 to prevent cardiac myocyte hypertrophy in female rodents.
机构信息
Division of Endocrinology, Department of Veterans Affairs Medical Center, Long Beach, CA, 90822, USA.
NIEHS, Research Triangle Park, NC, 27709, USA.
出版信息
Mol Cell Endocrinol. 2018 Jul 15;470:240-250. doi: 10.1016/j.mce.2017.11.004. Epub 2017 Nov 7.
Maintaining a healthy, anti-hypertrophic state in the heart prevents progression to cardiac failure. In humans, angiotensin II (AngII) indirectly and directly stimulates hypertrophy and progression, while estrogens acting through estrogen receptor beta (ERβ) inhibit these AngII actions. The KLF15 transcription factor has been purported to provide anti-hypertrophic action. In cultured neonatal rat cardiomyocytes, we found AngII inhibited KLF1 expression and nuclear localization, substantially prevented by estradiol (E2) or β-LGND2 (β-LGND2), an ERβ agonist. AngII stimulation of transforming growth factor beta expression in the myocytes activated p38α kinase via TAK1 kinase, inhibiting KLF15 expression. All was comparably reduced by E2 or β-LGND2. Knockdown of KLF15 in the myocytes induced myocyte hypertrophy and limited the anti-hypertrophic actions of E2 and β-LGND2. Key aspects were confirmed in an in-vivo model of cardiac hypertrophy. Our findings define additional anti-hypertrophic effects of ERβ supporting testing specific receptor agonists in humans to prevent progression of cardiac disease.
保持心脏健康、防止心肌肥大可以预防心力衰竭。在人体中，血管紧张素 II（AngII）通过间接和直接的作用刺激心肌肥大和进展，而雌激素通过雌激素受体 β（ERβ）发挥作用抑制这些 AngII 作用。KLF15 转录因子被认为具有抗心肌肥大作用。在培养的新生大鼠心肌细胞中，我们发现 AngII 抑制 KLF15 的表达和核定位，而雌二醇（E2）或 ERβ激动剂 β-LGND2 则可显著阻止这一作用。AngII 刺激心肌细胞中的转化生长因子-β表达，通过 TAK1 激酶激活 p38α 激酶，从而抑制 KLF15 的表达。E2 或 β-LGND2 均可显著减少 KLF15 的表达。在心肌细胞中敲低 KLF15 会诱导心肌细胞肥大，并限制 E2 和 β-LGND2 的抗心肌肥大作用。这些发现已在心肌肥大的体内模型中得到证实。我们的研究结果为 ERβ 的抗心肌肥大作用提供了更多的证据，支持在人类中测试特定的受体激动剂以预防心脏病的进展。
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