Smyrnias Ioannis, Zhang Xiaohong, Zhang Min, Murray Thomas V A, Brandes Ralf P, Schröder Katrin, Brewer Alison C, Shah Ajay M
From the Department of Cardiology, Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
Hypertension. 2015 Mar;65(3):547-53. doi: 10.1161/HYPERTENSIONAHA.114.04208. Epub 2014 Dec 22.
The transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) controls a network of cytoprotective genes. Neither how Nrf2 is activated in the heart under hemodynamic overload nor its role and mechanism of action are known. This study aimed to investigate the activation and role of Nrf2 during chronic cardiac pressure overload. We first compared the responses of Nrf2(-/-) mice and wild-type littermates to chronic pressure overload. Hearts of Nrf2(-/-) mice showed impaired antioxidant gene expression, increased hypertrophy, and worse function compared with those of wild-type littermates after overload. Hearts of Nrf2(-/-) mice had increased mitochondrial DNA damage, a caspase 8/BH3-interacting domain death agonist-related cleavage of mitochondrial apoptosis-inducing factor, nuclear DNA damage, and cell death. Nrf2 activation was under the control of the endogenous reactive oxygen species-generating enzyme nicotinamide adenine dinucleotide phosphate oxidase-4, both in vivo and in vitro. In mice with cardiac-specific overexpression of nicotinamide adenine dinucleotide phosphate oxidase-4, Nrf2 deletion significantly attenuated their protective phenotype during chronic pressure overload. This study identifies nicotinamide adenine dinucleotide phosphate oxidase-4-dependent upregulation of Nrf2 as an important endogenous protective pathway that limits mitochondrial damage and apoptosis-inducing factor-related cell death in the heart under hemodynamic overload.
转录因子核因子红细胞衍生2样2（Nrf2）控制着一个细胞保护基因网络。目前尚不清楚在血流动力学过载情况下Nrf2在心脏中是如何被激活的，也不清楚其作用和作用机制。本研究旨在探讨慢性心脏压力过载期间Nrf2的激活及其作用。我们首先比较了Nrf2基因敲除小鼠和野生型同窝小鼠对慢性压力过载的反应。与野生型同窝小鼠相比，Nrf2基因敲除小鼠的心脏在过载后抗氧化基因表达受损、肥大增加且功能更差。Nrf2基因敲除小鼠的心脏线粒体DNA损伤增加，线粒体凋亡诱导因子出现与半胱天冬酶8/BH3相互作用结构域死亡激动剂相关的裂解，核DNA损伤及细胞死亡。在体内和体外，Nrf2的激活均受内源性活性氧生成酶烟酰胺腺嘌呤二核苷酸磷酸氧化酶4的控制。在心脏特异性过表达烟酰胺腺嘌呤二核苷酸磷酸氧化酶4的小鼠中，Nrf2缺失显著减弱了它们在慢性压力过载期间的保护表型。本研究确定了烟酰胺腺嘌呤二核苷酸磷酸氧化酶4依赖性的Nrf2上调是一种重要的内源性保护途径，可限制血流动力学过载情况下心脏中的线粒体损伤和凋亡诱导因子相关的细胞死亡。
