Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29208, USA.
Cardiovasc Res. 2011 May 1;90(2):315-24. doi: 10.1093/cvr/cvr010. Epub 2011 Jan 18.
Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to be a negative regulator of maladaptive cardiac remodelling and dysfunction; however, a potential of the Nrf2-mediated cardiac protection in diverse pathological settings remains to be determined. This study was aimed to explore the role of Nrf2 in angiotensin II (Ang II)-induced cardiac hypertrophy.
Littermate wild-type (WT) and Nrf2 knockout (Nrf2(-/-)) mice were administered Ang II via osmotic mini-pumps for 2 weeks to induce cardiac hypertrophy. Elevation of blood pressure by the continuous Ang II infusion was comparable between WT and Nrf2(-/-) mice. Relative to WT mice, however, Nrf2(-/-) mice exhibited exaggerated myocardial oxidative stress with an impaired induction of a group of antioxidant genes and increased cardiac hypertrophy in response to the sustained Ang II stimulation. In cultured cardiomyocytes, adenoviral overexpression of Nrf2 shRNA enhanced Ang II-induced reactive oxygen species (ROS) production and protein synthesis, whereas adenoviral overexpression of Nrf2 exerted opposite effects. Moreover, Nrf2 deficiency exacerbated Ang II-induced down-regulation of p27(kip1) expression in the heart via a mechanism of post-transcriptional regulation. In contrast, adenoviral overexpression of Nrf2 increased p27(kip1) protein but not mRNA expression and reversed Ang II-induced down-regulation of p27(kip1) protein expression in cultured cardiomyocytes by suppressing ROS formation. Finally, the enhancement of Ang II-induced hypertrophic growth due to the Nrf2 deficiency was negated by overexpressing p27(kip1) in cultured cardiomyocytes.
The Nrf2-p27(kip1) pathway serves as a novel negative feedback mechanism in Ang II-induced pathogenesis of cardiac hypertrophy, independent of changes in blood pressure.
核因子红细胞 2 相关因子 2（Nrf2）似乎是一种负向调节病理性心肌重构和功能障碍的因子；然而，Nrf2 介导的心脏保护在不同病理环境下的潜力仍有待确定。本研究旨在探讨 Nrf2 在血管紧张素 II（Ang II）诱导的心肌肥厚中的作用。
通过渗透微型泵向同窝野生型（WT）和 Nrf2 敲除（Nrf2(-/-)）小鼠输注 Ang II，持续 2 周以诱导心肌肥厚。持续 Ang II 输注引起的血压升高在 WT 和 Nrf2(-/-)小鼠之间无差异。然而，与 WT 小鼠相比，Nrf2(-/-)小鼠在持续 Ang II 刺激下表现出更严重的心肌氧化应激，一组抗氧化基因的诱导减弱，心肌肥厚增加。在培养的心肌细胞中，腺病毒过表达 Nrf2 shRNA 增强了 Ang II 诱导的活性氧（ROS）产生和蛋白合成，而腺病毒过表达 Nrf2 则产生相反的效果。此外，Nrf2 缺乏通过转录后调节机制加剧了 Ang II 诱导的心脏中 p27(kip1)表达的下调。相反，腺病毒过表达 Nrf2 通过抑制 ROS 形成增加了 p27(kip1)蛋白但不增加其 mRNA 表达，并逆转了 Ang II 诱导的培养心肌细胞中 p27(kip1)蛋白表达的下调。最后，在培养的心肌细胞中过表达 p27(kip1)可消除因 Nrf2 缺乏而增强的 Ang II 诱导的心肌肥厚。
Nrf2-p27(kip1)途径是 Ang II 诱导的心肌肥厚发病机制中的一种新的负反馈机制，独立于血压变化。
