Differential microRNA Expression and Regulation in the Rat Model of Post-Infarction Heart Failure

Liu, Xueyan; Meng, Heyu; Jiang, Chao; Yang, Sibao; Cui, Fengwen; Yang, Ping

doi:10.1371/journal.pone.0160920

Cited by 32 publications

(30 citation statements)

References 48 publications

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“…[ 42 – 47 ]. Therefore, dysregulation of (a) microRNA(s) due to extrinsic and/or intrinsic stress further adds to the severity of the disease [ 48 – 50 ]. This very fact can and is being capitalized for the potential therapeutic uses of microRNAs against cardiac diseases [ 43 , 48 , 51 – 55 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA miR-301a is a novel cardiac regulator of Cofilin-2

Rangrez

Hoppe²,

Kühn

et al. 2017

PLoS ONE

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Calsarcin-1 deficient mice develop dilated cardiomyopathy (DCM) phenotype in pure C57BL/6 genetic background (Cs1-ko) despite severe contractile dysfunction and robust activation of fetal gene program. Here we performed a microRNA microarray to identify the molecular causes of this cardiac phenotype that revealed the dysregulation of several microRNAs including miR-301a, which was highly downregulated in Cs1-ko mice compared to the wild-type littermates. Cofilin-2 (Cfl2) was identified as one of the potential targets of miR-301a using prediction databases, which we validated by luciferase assay and mutation of predicted binding sites. Furthermore, expression of miR-301a contrastingly regulated Cfl2 expression levels in neonatal rat ventricular cardiomyocytes (NRVCM). Along these lines, Cfl2 was significantly upregulated in Cs1-ko mice, indicating the physiological association between miR-301a and Cfl2 in vivo. Mechanistically, we found that Cfl2 activated serum response factor response element (SRF-RE) driven luciferase activity in neonatal rat cardiomyocytes and in C2C12 cells. Similarly, knockdown of miR301a activated, whereas, its overexpression inhibited the SRF-RE driven luciferase activity, further strengthening physiological interaction between miR-301a and Cfl2. Interestingly, the expression of SRF and its target genes was strikingly increased in Cs1-ko suggesting a possible in vivo correlation between expression levels of Cfl2/miR-301a and SRF activation, which needs to be independently validated. In summary, our data demonstrates that miR-301a regulates Cofilin-2 in vitro in NRVCM, and in vivo in Cs1-ko mice. Our findings provide an additional and important layer of Cfl2 regulation, which we believe has an extended role in cardiac signal transduction and dilated cardiomyopathy presumably due to the reported involvement of Cfl2 in these mechanisms.

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Section: Discussionmentioning

confidence: 99%

MicroRNA miR-301a is a novel cardiac regulator of Cofilin-2

Rangrez

Hoppe²,

Kühn

et al. 2017

PLoS ONE

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“…The 13 candidate miRNAs are predicted to interact with 8 out of the 45 proteins modulated by LVR [10], testifying that they are involved in LVR after MI. Moreover, 9 out of the 13 candidate miRNAs have been described as biomarkers of HF: miR-21-3p, miR-21-5p, miR-23a-3p, miR-29b-3p, miR-122, miR-133a, miR-145-5p, miR-222-3p and miR-320a [10,[15][16][17][18][19], confirming their potential as targets to predict HF ( Figure 1A). To prioritize candidate miRNAs with high relation specificity with LVR, we evaluated in vivo the association of the 13 candidate miRNAs with LVR after MI ( Figure 1B).…”

Section: Analysis Of the Protein-mirna Network Derived From Post-mi Rmentioning

confidence: 68%

Integrative System Biology Analyses Identify Seven Micrornas to Predict Heart Failure

Charrier

Cuvelliez²,

Dubois‐Deruy³

et al. 2019

Preprint

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Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI predict molecular insights of this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicts 13 miRNAs and 3 of these miRNAs were validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicts 24 miRNAs among 1310 molecules and 6 of these miRNAs were selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

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“…A previous study has shown that MiR-31a-5p is linked to colorectal cancer (23). Our more recent work revealed that the miR-31a-5p level was significantly higher in the hearts of rats with post-infarction HF than that in the sham group (24). However, the exact role of miR-31a-5p in the pathogenesis of HF remains uncertain.…”

Section: Introductionmentioning

confidence: 85%

MiR-31a-5p protects myocardial cells against apoptosis by targeting Tp53

et al. 2017

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The pathogenesis and progression of heart failure (HF) involves multiple mechanisms, including the increased activity of the renin-angiotensin-aldosterone system, apoptosis and differential expression of microRNAs (miRNAs/miRs). Our previous study revealed an increase in miR‑31a‑5p levels in the failing hearts of a rat HF model. In the present study, whether and how miR‑31a‑5p mediates angiotensin II (AngII)‑induced apoptosis in the cardiac H9C2 cell line, was investigated using molecular biological approaches, including reverse transcription followed by quantitative polymerase chain reaction, western blotting, RNA arrays, and mutagenesis. It was demonstrated that AngII stimulation increased apoptosis and decreased miR‑31a‑5p expression, which coincided with increased tumor protein p53 (Tp53) levels. Overexpression of miR‑31a‑5p significantly suppressed the AngII‑induced apoptotic rate and caspase‑3 activity, while suppression of miR‑31a‑5p did the opposite. A total of 16 proapoptotic genes that were downregulated and 4 antiapoptotic genes that were upregulated in the miR‑31a‑5p‑overexpressed cells were identified. It was also revealed that Tp53 mRNA contained the seed sequence in its 3'‑untranslated region for miR‑31a‑5p binding. The luciferase reporter analysis showed that miR‑31a‑5p repressed the luciferase activity of the wild‑type seed sequence, but not the mutated seed sequence fused to a reporter construct. Thus, it was demonstrated that miR‑31a‑5p mediated AngII‑triggered apoptosis in myocardial cells at least partially through targeting Tp53. These findings advance the understanding of the functional interaction between miRNAs and Tp53 in the setting of cardiac diseases. Further work is required to explore whether miR‑31a‑5p can serve as a therapeutic target for HF treatment in vivo.

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Differential microRNA Expression and Regulation in the Rat Model of Post-Infarction Heart Failure

Abstract: Background

Cited by 32 publications

References 48 publications

MicroRNA miR-301a is a novel cardiac regulator of Cofilin-2

MicroRNA miR-301a is a novel cardiac regulator of Cofilin-2

Integrative System Biology Analyses Identify Seven Micrornas to Predict Heart Failure

MiR-31a-5p protects myocardial cells against apoptosis by targeting Tp53

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