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Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy.

ABSTRACT: Apoptosis is a hallmark of multiple etiologies of heart failure, including dilated cardiomyopathy. Since microRNAs are master regulators of cardiac development and key effectors of intracellular signaling, they represent novel candidates for understanding the mechanisms driving the increased dysfunction and loss of cardiomyocytes during cardiovascular disease progression. To determine the role of cardiac miRNAs in the apoptotic response, we used microarray technology to monitor miRNA levels in a validated murine phospholambam mutant model of dilated cardiomyopathy. 24 miRNAs were found to be differentially expressed, most of which have not been previously linked to dilated cardiomyopathy. We showed that individual silencing of 7 out of 8 significantly down-regulated miRNAs (mir-1, -29c, -30c, -30d, -149, -486, -499) led to a strong apoptotic phenotype in cell culture, suggesting they repress pro-apoptotic factors. To identify putative miRNA targets most likely relevant to cell death, we computationally integrated transcriptomic, proteomic and functional annotation data. We showed the dependency of prioritized target abundance on miRNA expression using RNA interference and quantitative mass spectrometry. We concluded that down regulation of key pro-survival miRNAs causes up-regulation of apoptotic signaling effectors that contribute to cardiac cell loss, potentially leading to system decompensation and heart failure.

SUBMITTER: Isserlin R

PROVIDER: S-EPMC4856157 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy.

Isserlin Ruth R Merico Daniele D Wang Dingyan D Vuckovic Dajana D Bousette Nicolas N Gramolini Anthony O AO Bader Gary D GD Emili Andrew A

Molecular bioSystems 20141031 1

Apoptosis is a hallmark of multiple etiologies of heart failure, including dilated cardiomyopathy. Since microRNAs are master regulators of cardiac development and key effectors of intracellular signaling, they represent novel candidates for understanding the mechanisms driving the increased dysfunction and loss of cardiomyocytes during cardiovascular disease progression. To determine the role of cardiac miRNAs in the apoptotic response, we used microarray technology to monitor miRNA levels in a ...[more]

PMID: 25361207

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Project description:AimsMildly dilated cardiomyopathy (MDCM) was characterized as a subset of dilated cardiomyopathy (DCM) with systolic dysfunction and modest ventricular dilatation, of which the prognostic studies were limited. We aimed to compare the prognostic value of the N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) between MDCM and DCM.Methods and resultsWe retrospectively included hospitalized patients diagnosed with DCM and a left ventricular ejection fraction ≤ 50% at Fuwai Hospital from 2006 to 2017. MDCM was defined as left ventricular end-diastolic diameter index (LVEDDi) ≤ 33 mm/m2 in males and ≤34 mm/m2 in females. A total of 640 patients (median age 49 years, 24.8% female) were included in this study. At baseline, 110 cases (17%) were categorized as MDCM and 529 cases (83%) as DCM. Of 282 patients who had follow-up echocardiograms ≥ 6 months, 7 MDCM patients (11.1%) evolved to DCM and 70 DCM patients (32.0%) recovered to MDCM by the change of LVEDDi. Compared with DCM, patients with baseline MDCM had lower composite risks of all-cause mortality, heart transplantation, and heart failure rehospitalization [adjusted hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.43-0.93, P = 0.019]. Both hs-CRP and NT-proBNP were independently associated with the composite endpoint in the overall cohort (hs-CRP: adjusted HR 1.07, 95% CI 1.00-1.15, P = 0.036; NT-proBNP: adjusted HR 1.11, 95% CI 1.02-1.22, P = 0.019). After a propensity-score matching between MDCM and DCM, higher NT-proBNP (above the median) was significantly associated with the outcome in DCM patients (HR 1.83, 95% CI 1.05-3.20, P = 0.034), but not in MDCM patients (HR 1.54, 95% CI 0.76-3.11, P = 0.227). On the contrary, higher hs-CRP (above the median) showed prognostic value for adverse events in MDCM patients (HR 3.19, 95% CI 1.52-6.66, P = 0.002), but not in DCM patients (HR 1.04, 95% CI 0.61-1.79, P = 0.88).ConclusionsIn patients with MDCM, although no evidence suggested the prognostic role of NT-proBNP, higher level of hs-CRP was associated with outcome, supporting the use of hs-CRP in risk stratification for patients with MDCM.

Project description:Hypertrophic/dilated cardiomyopathy, often a prequel to heart failure, is accompanied by maladaptive transcriptional changes that contribute to arrythmias and contractile misfunction. Transgenic mice constitutively expressing high levels of calcineurin are known to develop extreme heart hypertrophy, which progresses to dilated cardiomyopathy, and to die several weeks after birth. Here, we characterized aberrant transcriptional and epigenetic pathways in this mouse model and established a pharmacological approach to treat established cardiomyopathy. We found that H3K4me3 (trimethyl histone 3 lysine 4) and H3K9me3 (trimethyl histone 3 lysine 9) Jumonji histone demethylases are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. These epigenetic regulators continued to increase with time, further affecting cardiac gene expression. Our findings parallel the lower H3K4me3 and H3K9me3 levels seen in human patients. Inhibition of Jumonji demethylase activities in vivo results in lower histone demethylase enzymatic function in the heart and higher histone methylation levels and leads to partial reduction of heart size, reversal of maladaptive transcriptional programs, improved heart function, and prolonged survival. At the molecular level, target genes of transcription factor myocyte enhancer factor 2 are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases. Similar transcriptional reversal of disease-associated genes is seen in a second disease model based on cardiac mechanical overload. Our findings validate pharmacological inhibitors of Jumonji demethylases as potential therapeutics for the treatment of cardiomyopathies across disease models and provide evidence of the reversal of maladaptive transcriptional reprogramming leading to partial restoration of cardiac function. In addition, this study defines pathways of therapeutic resistance upregulated with disease progression.

Dataset Information

Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy.

Publications

Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy.

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