Nrf2 Protects Against Maladaptive Cardiac Responses to Hemodynamic Stress
Nrf2 Protects Against Maladaptive Cardiac Responses to Hemodynamic Stress
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DOI：
10.1161/atvbaha.109.189480
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发表时间：
2009-11-01
影响因子：
8.7
通讯作者：
Cui, Taixing
中科院分区：
文献类型：
--
作者：
Li, Jinqing;Ichikawa, Tomonaga;Cui, Taixing
背景-活性氧物种(ROS)在维持心血管内环境平衡中起着重要作用。本研究旨在确定核因子红系相关因子2(Nrf2)是内源性抗氧化防御系统的主要基因，是否是心脏对病理性应激肥大反应的关键调节因子。方法与结果-通过横动脉缩窄(TAC)建立小鼠心肌肥厚和功能障碍模型。随着心功能损害的进展，NRF2的表达一过性增加，然后下降到基础水平。敲除Nrf2(Nrf2(-/-))在非应激心脏中没有引起任何明显的结构和功能异常。然而，TAC后Nrf2(-/-)小鼠出现病理性心肌肥厚、显著的心肌纤维化和细胞凋亡、明显的心力衰竭和死亡率增加，这与心肌4-羟基-2-壬烯醛和8-羟基脱氧鸟苷水平升高以及几种抗氧化基因的表达完全阻断有关。Nrf2的过表达显著抑制了肥厚因子诱导的心肌细胞和心脏成纤维细胞中ROS的产生和生长，而Nrf2的过表达在两种细胞中都产生了相反的作用。结论：这些结果表明，Nrf2的激活提供了一种新的机制，通过抑制氧化应激来保护小鼠心脏免受病理性心肌肥大和心力衰竭的影响。(动脉血栓血管生物)2009；29：1843-1850。)
Background-Reactive oxygen species (ROS) play an important role in the maintenance of cardiovascular homeostasis. The present study sought to determine whether nuclear factor erythroid-2 related factor 2 (Nrf2), a master gene of the endogenous antioxidant defense system, is a critical regulator of the cardiac hypertrophic response to pathological stress.Methods and Results-Cardiac hypertrophy and dysfunction were established in mice by transverse aortic constriction (TAC). Nrf2 expression was transiently increased and then declined to the basal level while impairment of cardiac function proceeded. The knockout of Nrf2 (Nrf2(-/-)) did not cause any apparent structural and functional abnormalities in the unstressed heart. However, Nrf2(-/-) mice after TAC developed pathological cardiac hypertrophy, significant myocardial fibrosis and apoptosis, overt heart failure, and increased mortality, which were associated with elevated myocardial levels of 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine and a complete blockade of the myocardial expression of several antioxidant genes. Overexpression of Nrf2 dramatically inhibited hypertrophic factor-induced ROS production and growth in both cardiomyocytes and cardiac fibroblasts, whereas knockdown of Nrf2 exerted opposite effects in both cells.Conclusions-These findings demonstrate that activation of Nrf2 provides a novel mechanism to protect the murine heart against pathological cardiac hypertrophy and heart failure via suppressing oxidative stress. (Arterioscler Thromb Vasc Biol. 2009; 29: 1843-1850.)