Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation
Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation
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孤儿核受体 Nur77 抑制心脏对 β-肾上腺素能刺激的肥厚反应。
DOI：
10.1128/mcb.00229-15
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发表时间：
2015-10-01
影响因子：
5.3
通讯作者：
Sun, Jianxin
中科院分区：
文献类型：
--
作者：
Yan, Guijun;Zhu, Ni;Sun, Jianxin
孤儿核受体Nur 77在心血管疾病中起关键作用，并且其表达在β-肾上腺素能受体（β-AR）激活后在心脏中被显著诱导。然而，Nur 77在心脏β-AR信号传导中的功能意义仍不清楚。通过使用北方印迹，Western印迹和免疫荧光染色分析，我们发现，Nur 77的表达显着上调，在心肌细胞响应多种肥大刺激，包括异丙肾上腺素（ISO），苯肾上腺素（PE），内皮素-1（ET-1）。ISO以时间和剂量依赖性方式增加心肌细胞核中Nur 77的表达。过表达Nur 77可诱导心肌细胞Nur 77核转位，从而显著抑制ISO诱导的心肌肥大。此外，心肌内注射Ad-Nur 77的心脏过表达Nur 77显著抑制了ISO慢性输注后小鼠的心脏肥大，并改善了心功能障碍。从机制上讲，我们证明了Nur 77与NFATc 3和GATA 4在功能上相互作用，并抑制它们的转录活性，这对心脏肥大的发展至关重要。这些结果首次证明Nur 77是通过抑制NFATc 3和GATA 4转录途径而对β-AR诱导的心脏肥大的新的负调节剂。靶向Nur 77可能代表预防心脏肥大和心力衰竭的潜在新治疗策略。
The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (beta-AR) activation. However, the functional significance of Nur77 in beta-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time- and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the beta-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure.