Long noncoding RNAs in cardiac development and ageing.

A large part of the mammalian genome is transcribed into noncoding RNAs. Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators of gene expression. Distinct molecular mechanisms allow lncRNAs either to activate or to repress gene expression, thereby participating in the regulation of cellular and tissue function. LncRNAs, therefore, have important roles in healthy and diseased hearts, and might be targets for therapeutic intervention. In this Review, we summarize the current knowledge of the roles of lncRNAs in cardiac development and ageing. After describing the definition and classification of lncRNAs, we present an overview of the mechanisms by which lncRNAs regulate gene expression. We discuss the multiple roles of lncRNAs in the heart, and focus on the regulation of embryonic stem cell differentiation, cardiac cell fate and development, and cardiac ageing. We emphasize the importance of chromatin remodelling in this regulation. Finally, we discuss the therapeutic and biomarker potential of lncRNAs.

Identification of candidate long non-coding RNAs in response to myocardial infarction.

BACKGROUND: Long non-coding RNAs (lncRNAs) constitute a novel class of non-coding RNAs. LncRNAs regulate gene expression, thus having the possibility to modulate disease progression. In this study, we investigated the changes of lncRNAs expression in the heart after myocardial infarction (MI). RESULTS: Adult male C57/BL6 mice were subjected to coronary ligation or sham operation. In a derivation group of 4 MI and 4 sham-operated mice sacrificed 24 hours after surgery, microarray analysis showed that MI was associated with up-regulation of 20 lncRNAs and down-regulation of 10 lncRNAs (fold-change >2). Among these, 2 lncRNAs, called myocardial infarction-associated transcript 1 (MIRT1) and 2 (MIRT2), showed robust up-regulation in the MI group: 5-fold and 13-fold, respectively. Up-regulation of these 2 lncRNAs after MI was confirmed by quantitative PCR in an independent validation group of 8 MI and 8 sham-operated mice (9-fold and 16-fold for MIRT1 and MIRT2, P < 0.001). In a time-course analysis involving 21 additional MI mice, the expression of both lncRNAs peaked 24 hours after MI and returned to baseline after 2 days. In situ hybridization revealed an up-regulation of MIRT1 expression in the left ventricle of MI mice. Expression of MIRT1 and MIRT2 correlated with the expression of multiple genes known to be involved in left ventricular remodeling. Mice with high level of expression of MIRT1 and MIRT2 had a preserved ejection fraction. CONCLUSION: Myocardial infarction induces important changes in the expression of lncRNAs in the heart. This study motivates further investigation of the role of lncRNAs in left ventricular remodeling.

Cardioprotective effects of adenosine within the border and remote areas of myocardial infarction.

BACKGROUND: Adenosine may have beneficial effects on left ventricular function after myocardial infarction (MI), but the magnitude of this effect on remote and MI areas is controversial. We assessed the long-term effects of adenosine after MI using electrocardiogram-triggered 18 F-fluorodeoxyglucose positron emission tomography. METHODS: Wistar rats were subjected to coronary ligation and randomized into three groups treated daily for 2 months by NaCl (control; n = 7), 2-chloroadenosine (CADO; n = 8) or CADO with 8-sulfophenyltheophilline, an antagonist of adenosine receptors (8-SPT; n = 8). RESULTS: After 2 months, control rats exhibited left ventricular remodelling, with increased end-diastolic volume and decreased ejection fraction. Left ventricular remodelling was not significantly inhibited by CADO. Segmental contractility, as assessed by the change in myocardial thickening after 2 months, was improved in CADO rats compared to control rats (+1.6% ± 0.8% vs. -2.3% ± 0.8%, p < 0.001). This improvement was significant in border (+5.6% ± 0.8% vs. +1.5% ± 0.8%, p < 0.001) and remote (-4.0% ± 1.0% vs. -10.4% ± 1.3%, p < 0.001) segments, but absent in MI segments. Histological analyses revealed that CADO reduced fibrosis, cardiomyocyte hypertrophy and apoptosis. Protective effects of CADO were blunted by 8-SPT. CONCLUSION: Long-term administration of adenosine protects the left ventricle from contractile dysfunction following MI.

MicroRNA-150: a novel marker of left ventricular remodeling after acute myocardial infarction.

BACKGROUND: Left ventricular (LV) remodeling after acute myocardial infarction is associated with adverse prognosis. MicroRNAs (miRNAs) regulate the expression of several genes involved in LV remodeling. Our aim was to identify miRNAs associated with LV remodeling after acute myocardial infarction. METHODS AND RESULTS: We studied 90 patients after first ST-segment-elevation acute myocardial infarction. A derivation cohort consisted of 60 patients characterized by echocardiography predischarge and at 6-month follow-up. Thirty patients characterized by magnetic resonance imaging predischarge and at 4-month follow-up were the validation cohort. Remodeling was defined as an increase in LV end-diastolic volume (ΔEDV>0) between discharge and follow-up. Circulating miRNAs were measured by microarrays and polymerase chain reaction. Using a systems-based approach, we identified several miRNAs potentially involved in LV remodeling. In the derivation cohort, one of these miRNAs, miR-150, was downregulated in patients with remodeling (ΔEDV>0) compared with patients without remodeling (ΔEDV≤0). In the validation cohort, patients with remodeling had 2-fold lower levels of miR-150 than those without (P=0.03). miR-150 outperformed N-terminal pro-brain natriuretic peptide to predict remodeling (area under the receiver-operating characteristic curve of 0.74 and 0.60, respectively). miR-150 reclassified 54% (95% confidence interval, 5-102; P=0.03) of patients misclassified by N-terminal pro-brain natriuretic peptide and 59% (95% confidence interval, 9-108; P=0.02) of patients misclassified by a multiparameter clinical model, including age, sex, and admission levels of troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide. CONCLUSIONS: Low circulating levels of miR-150 are associated with LV remodeling after first ST-segment-elevation acute myocardial infarction. miR-150 has potential as a novel biomarker in this setting.