Hendgen-Cotta Ulrike B, Messiha Daniel, Esfeld Sonja, Deenen René, Rassaf Tienush, Totzeck Matthias
a Department of Cardiology and Angiology, Medical Faculty , West German Heart and Vascular Center Essen, University Hospital Essen , Essen , Germany.
b Biological and Medical Research Center (BMFZ), Heinrich-Heine-University , Düsseldorf , Germany.
Free Radic Res. 2017 Jan;51(1):91-102. doi: 10.1080/10715762.2017.1282158.
Acute myocardial infarction is the leading cause of mortality in the industrialized world. While it is essential to attempt an early reperfusion of ischemic myocardial territories, reperfusion itself adds damage to the heart, the ischemia-reperfusion (I/R) injury. Particularly the injury resulting from the very first minutes of reperfusion remains incompletely understood. MicroRNAs (miRNAs) are dynamic regulators in I/R injury. Nitric oxide (•NO) signaling, in turn, interacts with miRNA signaling. Our previous investigations showed that •NO signaling in I/R could be modulated by nitrite. We therefore sought to investigate the role of miRNAs in nitrite cardioprotection with focus on the first few minutes of reperfusion. The study was conducted in mice in vivo with 30 min of ischemia and 5 min of reperfusion. Mice received a single-dose of nitrite or saline intracardially 5 min prior to reperfusion. We identified nine miRNAs to be up-regulated after 5 min of reperfusion. The up-regulation of almost half of those miRNAs (miR-125a-5p, miR-146b, miR-339-3p, miR-433) was inhibited by nitrite treatment, perpetuating baseline values. In silico analysis revealed the Irak-M gene to be a target of miR-146b and miR-339-3p. Correspondingly, a rise in Irak-M transcript and protein levels occurred by nitrite treatment within the early phase of reperfusion. The results demonstrate that already a very short phase of reperfusion is sufficient for significant dysregulation in cardiac miRNAs expression and that nitrite preserves baseline values of miRNAs in the scale of only a few minutes. These findings hint at a potential novel cardioprotective mechanism of nitrite signaling.
急性心肌梗死是工业化国家的主要死亡原因。虽然尽早对缺血心肌区域进行再灌注至关重要，但再灌注本身会给心脏增加损伤，即缺血再灌注（I/R）损伤。尤其是再灌注最初几分钟所导致的损伤仍未完全明确。微小RNA（miRNA）是I/R损伤中的动态调节因子。反过来，一氧化氮（•NO）信号传导与miRNA信号传导相互作用。我们之前的研究表明，I/R中的•NO信号传导可被亚硝酸盐调节。因此，我们试图研究miRNA在亚硝酸盐心脏保护中的作用，重点关注再灌注的最初几分钟。该研究在体内小鼠中进行，缺血30分钟，再灌注5分钟。小鼠在再灌注前5分钟经心内注射单剂量亚硝酸盐或生理盐水。我们鉴定出9种miRNA在再灌注5分钟后上调。亚硝酸盐处理可抑制其中近一半miRNA（miR-125a-5p、miR-146b、miR-339-3p、miR-433）的上调，使其维持在基线水平。计算机分析显示Irak-M基因是miR-146b和miR-339-3p的靶标。相应地，在再灌注早期，亚硝酸盐处理导致Irak-M转录本和蛋白水平升高。结果表明，即使是非常短暂的再灌注阶段也足以导致心脏miRNA表达出现显著失调，而亚硝酸盐在短短几分钟内就能维持miRNA的基线水平。这些发现提示了亚硝酸盐信号传导潜在的新型心脏保护机制。
