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Genome-wide profiling of the nascent transcription of non-coding RNAs in porcine heart after myocardial infarction

ABSTRACT: Very little information is available about non-coding(nc)RNAs and their role in regulating tissue responses in myocardial ischemia and acute infarction. We measured for the first time nascent RNA transcription of protein coding genes, primary(pri)-miRNAs, long non-coding(lnc)RNAs and enhancer(e)RNAs in healthy myocardium, border zone to ischemia and infarction area in pig hearts using GRO-seq. The gene expression analysis indicated a gradient of induction of inflammatory mediators, and repression of PPAR-signaling and oxidative phosphorylation. An exception to rule was A1 adenosine receptor, which exhibited induced gene expression in the border zone, where it might increase myocardial resistance to ischemia, but repression in the ischemic zone. In addition, we interrogated for the first time the transcriptional regulation of pri-miRs and provide evidence that several arrhythmia-related target genes are further repressed at post-transcriptional level. We identified 450 lncRNAs which were differently regulated by ischemia including novel lncRNAs expressed in antisense orientation to major myocardial transcription factors GATA4, GATA6 and KLF6. Finally, characterization of enhancers exhibiting differential expression of eRNAs, pointed a central role for KLF, MEF2C, ETS, NFY, ATF, E2F2 and NRF1 transcription factors in determining tissue-specific responses to ischemic insult. In conclusion, GRO-Seq allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel ncRNAs regulated by oxygen deprivation. These findings have identified potential new targets for diagnosis and treatment of myocardial ischemia based on acute changes in eRNA, lncRNA and miRNA expression in the affected heart.

ORGANISM(S): Sus scrofa

PROVIDER: GSE81155 | GEO | 2017/06/19

SECONDARY ACCESSION(S): PRJNA320748

REPOSITORIES: GEO

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Project description:Coronary heart disease is the leading cause of death worldwide. After an acute myocardial infarction, early reperfusion reduces infarct size, which correlates with improved clinical outcomes. Paradoxically, reperfusion although relieving ischemia, accelerates apoptosis in injured cardiomyocytes, which has led to the view that myocardial salvage is futile beyond the first few hours of reperfusion. In murine hearts subjected to 90 min of coronary artery occlusion and then 48 h of reperfusion, we show transient activation of intrinsic prosurvival insulin-like growth factor-1 (IGF-1) signaling. In these hearts, acute IGF-1 receptor inhibition decreases the abundance of prosurvival signaling molecules, and markedly activates caspase-3, a potent effector of apoptosis, in infarct border zone cardiomyocytes. We found that mouse mast cell protease-4 (MMCP-4) degraded IGF-1 in vitro by a novel catalytic activity of chymases. In vivo, this degradation, which is triggered by mast cell infiltration into the peri-infarct region and MMCP-4 extravasation, between 48 and 72 h post-ischemia/reperfusion (I/R), attenuates IGF-1 prosurvival signaling. In MMCP-4-deficient mice, while infarct size is not reduced at 24 h post-I/R, at 72 h post-I/R myocardial IGF-1 levels and signaling are increased, resulting in activation of the survival kinases Akt and ERK, inhibition of caspase-3, and reduced myocardial cell death. As a consequence, I/R-mediated loss of viable myocardium, adverse cardiac remodeling and contractile impairment are markedly reduced. Cardiomyocyte survival with consequent myocardial salvage may thus be possible even days after an ischemic insult, making them a novel therapeutic target for delayed cardioprotective therapy. Group 1 is wild type C57Bl6 uninjured hearts. These mice were not undergone any surgery and used as controls. Group 2 are wild type C57Bl6 72 h post-ischemia reperfusion (IR) injury hearts. These mice for subjected to ischemia reperfusion (IR) involving 90 min of left anterior descending coronary artery occlusion followed by reperfusion for 3 days or 72 h.

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Genome-wide profiling of the nascent transcription of non-coding RNAs in porcine heart after myocardial infarction

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