Nox1 NADPH oxidase is necessary for late but not early myocardial ischaemic preconditioning.
Nox1 NADPH oxidase is necessary for late but not early myocardial ischaemic preconditioning.
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DOI：
10.1093/cvr/cvu027
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发表时间：
2014-04
影响因子：
10.8
通讯作者：
Shuxia Jiang;Jennifer Streeter;B. Schickling;Kathy A. Zimmerman;R. Weiss;F. Miller
中科院分区：
文献类型：
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作者：
Shuxia Jiang;Jennifer Streeter;B. Schickling;Kathy A. Zimmerman;R. Weiss;F. Miller
目的缺血预处理（IPC）是一种适应性机制，使心肌抵抗随后的缺氧损伤。虽然活性氧（ROS）在IPC的早期和晚期都有贡献，但它们的酶源和相关的信号事件尚未完全了解。我们的目的是研究Nox1 NADPH氧化酶在IPC提供的心脏保护中的作用。方法和结果野生型（WT）和nox1缺陷小鼠接受三个周期的短暂冠状动脉闭塞和再灌注，然后立即（IPC早期）或24小时后（IPC晚期）延长闭塞。Nox1缺乏对早期IPC提供的心脏保护没有影响。相比之下，与WT心脏相比，IPC晚期Nox1缺乏导致梗死面积增大、心脏重构和心肌凋亡增加。此外，Nox1在WT心脏中的表达随着晚期IPC的增加而增加。Nox1缺乏可消除晚期ipc介导的心核因子-κB （NF-κB）的激活和心脏和循环中肿瘤坏死因子-α (TNF-α)的诱导。最后，在体外培养的心肌细胞中，敲低Nox1可阻止TNF-α诱导的NF-κB和IPC对缺氧诱导的细胞凋亡的保护作用。结论：我们的数据确定了Nox1在晚期IPC中的关键作用，并确定了TNF-α和NF-κB在介导心肌损伤耐受中的先前未被认识的联系。考虑到Nox1抑制剂治疗心血管疾病的出现，这些发现具有临床意义。
AIMS Ischaemic preconditioning (IPC) is an adaptive mechanism that renders the myocardium resistant to injury from subsequent hypoxia. Although reactive oxygen species (ROS) contribute to both the early and late phases of IPC, their enzymatic source and associated signalling events have not yet been understood completely. Our objective was to investigate the role of the Nox1 NADPH oxidase in cardioprotection provided by IPC. METHODS AND RESULTS Wild-type (WT) and Nox1-deficient mice were treated with three cycles of brief coronary occlusion and reperfusion, followed by prolonged occlusion either immediately (early IPC) or after 24 h (late IPC). Nox1 deficiency had no impact on the cardioprotection afforded by early IPC. In contrast, deficiency of Nox1 during late IPC resulted in a larger infarct size, cardiac remodelling, and increased myocardial apoptosis compared with WT hearts. Furthermore, expression of Nox1 in WT hearts increased in response to late IPC. Deficiency of Nox1 abrogated late IPC-mediated activation of cardiac nuclear factor-κB (NF-κB) and induction of tumour necrosis factor-α (TNF-α) in the heart and circulation. Finally, knockdown of Nox1 in cultured cardiomyocytes prevented TNF-α induction of NF-κB and the protective effect of IPC on hypoxia-induced apoptosis. CONCLUSIONS Our data identify a critical role for Nox1 in late IPC and define a previously unrecognized link between TNF-α and NF-κB in mediating tolerance to myocardial injury. These findings have clinical significance considering the emergence of Nox1 inhibitors for the treatment of cardiovascular disease.