Circulating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning
Circulating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning
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DOI：
10.1161/circresaha.114.303822
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发表时间：
2014-05-09
影响因子：
20.1
通讯作者：
Kelm, Malte
中科院分区：
文献类型：
--
作者：
Rassaf, Tienush;Totzeck, Matthias;Kelm, Malte
基本原理：远端缺血预处理（remote ischemic preconditioning，rIPC）是一种有效的保护心肌缺血再灌注损伤的方法。远程站点和心脏之间的串扰的信号转导通路仍不清楚detailed.Objective：阐明循环亚硝酸盐在cardioprotection中的作用通过rIPC.Methods和Results：小鼠进行4个周期的无血流缺血与随后的反应性充血内股动脉区域和在体内进行心肌I/R（30分钟/5分钟或24小时）。使用遗传学和药理学方法进行小鼠实验。反应性充血过程中股动脉内内皮型一氧化氮合酶的剪切应力依赖性刺激产生大量的一氧化氮释放，随后氧化为亚硝酸盐，并通过体液转移到心肌。在心脏内，心肌肌红蛋白将亚硝酸盐还原为一氧化氮，随后线粒体膜蛋白发生S-亚硝化，从而减少线粒体呼吸、活性氧形成和心肌梗死面积。药理学和遗传学抑制一氧化氮/亚硝酸盐生成的内皮型一氧化氮合酶在远程网站或亚硝酸盐生物激活的肌红蛋白在靶器官废除的心脏保护rIPC。来自健康志愿者的血浆的转移实验受到手臂的rIPC鉴定血浆亚硝酸盐作为暴露于I/R的分离Langendorff小鼠心脏制备物中的心脏保护剂。结论：循环亚硝酸盐来源于在rIPC的远程站点处的内皮一氧化氮合酶的剪切应力依赖性刺激，有助于I/R期间的心脏保护。临床试验注册URL：http://www.clinicaltrials.gov。唯一标识符：NCT 01259739。
Rationale: Remote ischemic preconditioning (rIPC) with short episodes of ischemia/reperfusion (I/R) of an organ remote from the heart is a powerful approach to protect against myocardial I/R injury. The signal transduction pathways for the cross talk between the remote site and the heart remain unclear in detail.Objective: To elucidate the role of circulating nitrite in cardioprotection by rIPC.Methods and Results: Mice were subjected to 4 cycles of no-flow ischemia with subsequent reactive hyperemia within the femoral region and underwent in vivo myocardial I/R (30 minutes/5 minutes or 24 hours). The mouse experiments were conducted using genetic and pharmacological approaches. Shear stress-dependent stimulation of endothelial nitric oxide synthase within the femoral artery during reactive hyperemia yielded substantial release of nitric oxide, subsequently oxidized to nitrite and transferred humorally to the myocardium. Within the heart, reduction of nitrite to nitric oxide by cardiac myoglobin and subsequent S-nitrosation of mitochondrial membrane proteins reduced mitochondrial respiration, reactive oxygen species formation, and myocardial infarct size. Pharmacological and genetic inhibition of nitric oxide/nitrite generation by endothelial nitric oxide synthase at the remote site or nitrite bioactivation by myoglobin within the target organ abrogated the cardioprotection by rIPC. Transfer experiments of plasma from healthy volunteers subjected to rIPC of the arm identified plasma nitrite as a cardioprotective agent in isolated Langendorff mouse heart preparations exposed to I/R.Conclusions: Circulating nitrite derived from shear stress-dependent stimulation of endothelial nitric oxide synthase at the remote site of rIPC contributes to cardioprotection during I/R.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01259739.