An MRTF-A-Sp1-PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy.
An MRTF-A-Sp1-PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy.
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MRTF-A-Sp1-PDE5 轴介导血管紧张素 II 诱导的心肌细胞肥大
DOI：
10.3389/fcell.2020.00839
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发表时间：
2020
影响因子：
5.5
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Wu T;Wang H;Xin X;Yang J;Hou Y;Fang M;Lu X;Xu Y
心脏肥大是心力衰竭发病机制中的关键中间步骤。无数的信号网络聚集在心肌细胞上，以引起对各种有害刺激的肥大生长。在本研究中，我们研究了心肌细胞特异性的作用，心肌细胞相关转录因子A（MRTF-A）在血管紧张素II（Ang-II）诱导的心肌肥大和潜在的机制。我们报告了心肌细胞中条件性MRTF-A缺失可减轻Ang-II诱导的小鼠心肌肥大。类似地，MRTF-A敲低或抑制抑制培养的心肌细胞中Ang-II诱导的促肥大反应。值得注意的是，Ang II处理上调了心肌细胞中磷酸二酯酶5（PDE 5）的表达，这是一种已知的心脏肥大和心力衰竭的介质，可通过MRTF-A消耗或抑制来阻断。从机制上讲，MRTF-A激活特异性蛋白1（Sp1）的表达，Sp1又与PDE 5启动子结合，上调PDE 5转录，促进心肌细胞响应Ang II刺激的肥大。因此，我们的数据揭示了一种新的MRTF-A-Sp1-PDE 5轴，介导Ang-II诱导的心肌细胞肥大反应。靶向这一新发现的MRTF-A-Sp1-PDE 5轴可能会产生新的治疗心力衰竭的干预解决方案。
Cardiac hypertrophy is a critical intermediate step in the pathogenesis of heart failure. A myriad of signaling networks converge on cardiomyocytes to elicit hypertrophic growth in response to various injurious stimuli. In the present study, we investigated the cardiomyocyte-specific role of myocardin-related transcription factor A (MRTF-A) in angiotensin-II (Ang-II)-induced cardiac hypertrophy and the underlying mechanism. We report that conditional MRTF-A deletion in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice. Similarly, MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic response in cultured cardiomyocytes. Of note, Ang II treatment upregulated expression of phosphodiesterase 5 (PDE5), a known mediator of cardiac hypertrophy and heart failure, in cardiomyocytes, which was blocked by MRTF-A depletion or inhibition. Mechanistically, MRTF-A activated expression of specificity protein 1 (Sp1), which in turn bound to the PDE5 promoter and upregulated PDE5 transcription to promote hypertrophy of cardiomyocytes in response to Ang II stimulation. Therefore, our data unveil a novel MRTF-A–Sp1–PDE5 axis that mediates Ang-II-induced hypertrophic response in cardiomyocytes. Targeting this newly identified MRTF-A–Sp1–PDE5 axis may yield novel interventional solutions against heart failure.