Department of Pharmacology, Georgetown University, Washington, DC 20057, USA.
Hypertension. 2010 Dec;56(6):1145-51. doi: 10.1161/HYPERTENSIONAHA.110.160515. Epub 2010 Nov 8.
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 posttranslational 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 CCAAT-binding factor/nuclear factor-Y (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.
肺动脉高压患者的主要死亡原因是右心衰竭，但右心的生物学特性尚未被充分认识。先前的研究表明，左、右心室应对压力超负荷时 GATA4（一种心脏肥大的主要调节因子）激活的机制不同。在左心室，主动脉缩窄通过翻译后修饰触发 GATA4 激活，而不影响 GATA4 的表达，而肺动脉结扎则增强右心室中 GATA4 的表达。我们发现，慢性低氧诱导肺动脉高压的大鼠右心室中 GATA4 的表达也可以增加，并研究了 GATA4 表达增加的机制。对 Gata4 启动子的检查表明，CCAAT 盒在基因激活中起重要作用，低氧性肺动脉高压促进 CBF/NF-Y（CCAAT 结合因子/核因子-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。低氧性肺动脉高压时，膜联蛋白 A1 降解，导致 CBF/NF-Y 依赖的 Gata4 基因转录激活。与左心室相比，右心室含有更高水平的 CBF/NF-Y，这可能使其能够有效地对膜联蛋白 A1 降解做出反应。铁催化的蛋白氧化介导的信号通路介导低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厚。这些结果建立了一种针对压力超负荷的右心特异性信号机制，涉及铁催化的碳氧键形成和膜联蛋白 A1 的降解，释放 CBF/NF-Y 以激活 Gata4 基因转录。
