Analyses of changes in myocardial long non-coding RNA and mRNA profiles after severe hemorrhagic shock and resuscitation via RNA sequencing in a rat model

Abstract

BackgroundIschemia–reperfusion injury has been proven to induce organ dysfunction and death, although the mechanism is not fully understood. Long non-coding RNAs (lncRNAs) have drawn wide attention with their important roles in the gene expression of some biological processes and diseases, including myocardial ischemia–reperfusion (I/R) injury. In this paper, a total of 26 Sprague–Dawley (SD) rats were randomized into two groups: sham and ischemia–reperfusion (I/R) injury. Hemorrhagic shock was induced by removing 45% of the estimated total blood volume followed by reinfusion of shed blood. High-throughput RNA sequencing was used to analyze differentially expressed (DE) lncRNAs and messenger RNAs (mRNAs) in the heart tissue 4 h after reperfusion. Myocardial function was also evaluated.ResultsAfter resuscitation, the decline of myocardial function of shocked animals, expressed by cardiac output, ejection fraction, and myocardial performance index (MPI), was significant (p < 0.05). DE lncRNAs and mRNAs were identified by absolute value of fold change ≥ 2 and the false discovery rate ≤ 0.001. In rats from the I/R injury group, 851 lncRNAs and 1015 mRNAs were significantly up-regulated while 1533 lncRNAs and 1702 m RNAs were significantly down-regulated when compared to the sham group. Among the DE lncRNAs, we found 12 location-associated with some known apoptosis-related protein-coding genes which were up-regulated or down-regulated accordingly, including STAT3 and Il1r1. Real time PCR assays confirmed that the expression levels of five location-associated lncRNAs (NONRATT006032.2, NONRATT006033.2, NONRATT006034.2, NONRATT006035.2 and NONRATT029969.2) and their location-associated mRNAs (STAT3 and Il1r1) in the rats from the I/R injury group were all significantly up-regulated versus the sham group.ConclusionsThe DE lncRNAs (NONRATT006032.2, NONRATT006033.2, NONRATT006034.2 and NONRATT006035.2) could be compatible with their role in myocardial protection by stimulating their co-located gene (STAT3) after hemorrhagic shock and resuscitation. The final prognosis of I/R injury might be regulated by different genes, which is regarded as a complex network.Electronic supplementary materialThe online version of this article (10.1186/s12867-018-0113-8) contains supplementary material, which is available to authorized users.

Long noncoding RNAs: Important participants and potential therapeutic targets for myocardial ischaemia reperfusion injury

“…Studies in rodent models have shown that I/R causes dysregulated lncRNA expressions in cardiac tissue. [10][11][12] For instance, Liu 11 with a similar trend of changes observed in both of the cell culture and the cardiac tissue. Collectively, these results support the notion that I/R causes a dysregulation of the expression of cardiac lncRNAs.…”

“…Studies in rodent models have shown that I/R causes dysregulated lncRNA expressions in cardiac tissue 10‐12 . For instance, Liu et al 12 have found that 151 lncRNAs are differentially expressed (with 64 upregulated and 87 downregulated) in I/R‐treated myocardium from rats.…”

“…Among these dysregulated lncRNAs, 12 have been confirmed to be related to genes encoding for apoptosisrelated proteins such as STAT3 and IL1R1 10. Huang et al have explored the effect of I/R on lncRNA expressions inH9c2 myocytes and Langendorff-perfused hearts from rats, showing that 797 lncRNAs and 1,898 mRNAs are differentially expressed after I/R challenge,…”

Novel Molecular Targets Participating in Myocardial Ischemia-Reperfusion Injury and Cardioprotection

“…To investigate the mechanisms underlying potentially crucial molecular targets in MIRI for corresponding treatment, their expression in the myocardium at a genome-wide level must be determined [84, 110, 111]. Because of the complexity of MIRI-related pathophysiology, especially the diversity of potential sequence variants as well as the detectable epigenetic modifications that may alter the gene expression profiles among different participating cell populations [9, 10, 13], it is conceivable that genome biological techniques, such as high-throughput and high-resolution gene sequencing, might be more successful for detecting unidentified therapeutic targets and therefore better understanding the signaling network responsible for MIRI and cardioprotection [84, 110].…”

“…In contrast, the inhibition of Akt expression blocks the cardioprotection regulated by angiotensin (a crucial peptide hormone in the cardiovascular system) both in vitro and ex vivo [132], suggesting that AT2R functioning as a receptor for angiotensin II may mediate Akt activation during cardioprotection against MIRI. However, despite this influx of recent findings, much remains unclear regarding the genetically active loci of the genome associated with MIRI and cardioprotection [110, 111].…”