Pulmonary hypertension-induced GATA4 activation in the right ventricle.
Pulmonary hypertension-induced GATA4 activation in the right ventricle.
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DOI：
10.1161/hypertensionaha.110.160515
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Suzuki YJ
中科院分区：
文献类型：
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作者：
Park AM;Wong CM;Jelinkova L;Liu L;Nagase H;Suzuki YJ
肺动脉高压患者死亡的主要原因是右心衰竭，但右心的生物学机制尚不清楚。先前的研究表明，左心室和右心室响应压力超负荷而激活 GATA4（心脏肥大的主要调节因子）的机制不同。在左心室中，主动脉缩窄通过翻译后修饰触发 GATA4 激活，而不影响 GATA4 表达，而肺动脉束带则增强右心室中的 GATA4 表达。我们发现慢性缺氧诱发肺动脉高压的大鼠右心室中GATA4表达也可以增加，并研究了GATA4表达增加的机制。对Gata4启动子的检查表明CCAAT盒在基因激活中发挥着重要作用；缺氧性肺动脉高压促进CBF/NF-Y与右心室CCAAT盒的结合。我们发现 CBF/NF-Y 与膜联蛋白 A1 形成复合物，抑制 DNA 结合活性。为了应对缺氧性肺动脉高压，膜联蛋白 A1 被降解，导致 Gata4 基因转录的 CBF/NF-Y 依赖性激活。与左心室相比，右心室含有更高水平的 CBF/NF-Y，这可能允许有效激活以响应膜联蛋白 A1 降解。通过铁催化的蛋白质氧化信号传导，介导缺氧性肺动脉高压诱导的膜联蛋白 A1 降解、Gata4 基因转录和右心室肥大。这些结果建立了一种响应压力过载的右心特异性信号传导机制，其中涉及金属催化的羰基化和膜联蛋白 A1 的降解，从而释放 CBF/NF-Y 来激活 Gata4 基因转录。
The major cause of death among pulmonary hypertension patients is right heart failure, but the biology of right heart is not well understood. Previous studies showed that mechanisms of the activation of GATA4, a major regulator of cardiac hypertrophy, in response to pressure overload are different between left and right ventricles. In the left ventricle, aortic constriction triggers GATA4 activation via post-translational modifications without influencing GATA4 expression, while pulmonary artery banding enhances GATA4 expression in the right ventricle. We found that GATA4 expression can also be increased in the right ventricle of rats treated with chronic hypoxia to induce pulmonary hypertension, and investigated the mechanism of increased GATA4 expression. Examination of Gata4 promoter revealed that CCAAT box plays an important role in gene activation; and hypoxic pulmonary hypertension promoted the binding of CBF/NF-Y to CCAAT box in the right ventricle. We found that CBF/NF-Y forms a complex with annexin A1, which inhibits DNA binding activity. In response to hypoxic pulmonary hypertension, annexin A1 gets degraded, resulting in CBF/NF-Y-dependent activation of Gata4 gene transcription. The right ventricle contains a higher level of CBF/NF-Y compared to the left ventricle, and this may allow for efficient activation in response to annexin A1 degradation. Signaling via iron-catalyzed protein oxidation, mediates hypoxic pulmonary hypertension-induced annexin A1 degradation, Gata4 gene transcription, and right ventricular hypertrophy. These results establish a right heart-specific signaling mechanism in response to pressure overload, which involves metal-catalyzed carbonylation and degradation of annexin A1 that liberates CBF/NF-Y to activate Gata4 gene transcription.