Inorganic nitrite modulates miRNA signatures in acute myocardial in vivo ischemia/reperfusion

Abstract

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. ARTICLE HISTORY

miR-125a, miR-139 and miR-324 contribute to Urocortin protection against myocardial ischemia-reperfusion injury

“…The role of miR-125a-3p, miR-324-3p, and miR-139-3p in cardioprotection is still unclear. Previous reports demonstrated that circulating miR-125a-5p was associated with heart failure 29 , and it was significantly upregulated in early phase of reperfusion in mice 30 . An other recent study demonstrated that miR-139-5p is downregulated in left ventricular tissue isolated from patients undergoing remote conditioning 31 .…”

MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage

“…Further, for miR qRT-PCR data, a fold change of 1.2 is generally used as cutoff instead of the 2-fold cutoff for mRNAs, since it is believed that small differences in miR levels are sufficient for the fine-tuning of the transcriptional system executed by miRs. Various studies have shown miRs with a fold change ~1.2 to be biologically relevant [ 31 , 32 ].…”

miR‐200a mediates protection of thymosin β‐4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia‐reoxygenation injury

“…MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that could modulate gene expression post‐transcriptionally, leading to mRNA degradation or translational inhibition . Progressive evidence indicates that the abnormal levels of miRNAs occur in myocardial infarction, which are involved in regulating the oxidative stress and inflammation in MIRI .…”

“…MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that could modulate gene expression post-transcriptionally, leading to mRNA degradation or translational inhibition. 12 Progressive evidence indicates that the abnormal levels of miRNAs occur in myocardial infarction, which are involved in regulating the oxidative stress and inflammation in MIRI. 13,14 miRNA-200a is found to protect myocardial cells against hypoxia-induced apoptosis through activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.…”