Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function
Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function
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DOI：
10.1016/j.freeradbiomed.2015.10.409
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发表时间：
2015-12-01
影响因子：
7.4
通讯作者：
Cortese-Krott, Miriam M.
中科院分区：
文献类型：
--
作者：
Erkens, Ralf;Kramer, Christian M.;Cortese-Krott, Miriam M.
活性氧的产生增加和抗氧化防御系统的失效被认为在心血管疾病的发病机制中起着核心作用。转录因子核因子类2(Nrf2)是控制抗氧化剂和保护酶表达的关键主开关，被认为参与了血管和心脏功能的保护。本研究旨在分析缺乏Nrf2基因的小鼠的心脏和血管表型。我们发现Nrf2基因敲除(Nrf2KO)小鼠存在左室舒张功能障碍，超声心动图显示E波减速时间、松弛时间和总舒张期延长，E/A比值和心肌功能指数增加。Nrf2KO小鼠的左心功能障碍与心肌肥厚和心肌肌浆网钙-三磷酸腺苷酶(SERCA2a)的下调有关。因此，心脏松弛受到损害，表现为体外对异丙肾上腺素能刺激的反应降低，以及体内对心苷哇巴因的反应降低。令人惊讶的是，我们发现Nrf2KO小鼠的血管内皮功能和内皮型一氧化氮合酶(ENOS)介导的血管反应完全保留，血压下降，eNOS在主动脉和心脏上调。综上所述，这些结果表明，Nrf2KO小鼠的左心功能障碍主要与心肌肥厚和SERCA2a的下调有关，而不依赖于冠状动脉血管功能或全身血流动力学的变化，而这些变化是通过eNOS的代偿性上调来维持的。这些数据为Nrf2的表达/功能如何影响心血管系统提供了新的见解。(C)2015年提交人。由爱思唯尔公司出版。
Increased production of reactive oxygen species and failure of the antioxidant defense system are considered to play a central role in the pathogenesis of cardiovascular disease. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch controlling the expression of antioxidant and protective enzymes, and was proposed to participate in protection of vascular and cardiac function. This study was undertaken to analyze cardiac and vascular phenotype of mice lacking Nrf2. We found that Nrf2 knock out (Nrf2 KO) mice have a left ventricular (LV) diastolic dysfunction, characterized by prolonged E wave deceleration time, relaxation time and total diastolic time, increased E/A ratio and myocardial performance index, as assessed by echocardiography. LV dysfunction in Nrf2 KO mice was associated with cardiac hypertrophy, and a downregulation of the sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) in the myocardium. Accordingly, cardiac relaxation was impaired, as demonstrated by decreased responses to beta-adrenergic stimulation by isoproterenol ex vivo, and to the cardiac glycoside ouabain in vivo. Surprisingly, we found that vascular endothelial function and endothelial nitric oxide synthase (eNOS)-mediated vascular responses were fully preserved, blood pressure was decreased, and eNOS was upregulated in the aorta and the heart of Nrf2 KO mice. Taken together, these results show that LV dysfunction in Nrf2 KO mice is mainly associated with cardiac hypertrophy and downregulation of SERCA2a, and is independent from changes in coronary vascular function or systemic hemodynamics, which are preserved by a compensatory upregulation of eNOS. These data provide new insights into how Nrf2 expression/function impacts the cardiovascular system. (C) 2015 The Authors. Published by Elsevier Inc.