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Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure.

ABSTRACT: RATIONALE: Heart failure is a deadly and devastating disease that places immense costs on an aging society. To develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. OBJECTIVE: microRNAs are important regulators of gene expression, and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. METHODS AND RESULTS: First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Second, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8, a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality. CONCLUSIONS: These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs may ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8.

ORGANISM(S): Mus musculus

PROVIDER: GSE32881 | GEO | 2011/10/12

SECONDARY ACCESSION(S): PRJNA146611

REPOSITORIES: GEO

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Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure.

Project description:RATIONALE: Heart failure is a deadly and devastating disease that places immense costs on an aging society. To develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. OBJECTIVE: microRNAs are important regulators of gene expression, and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. METHODS AND RESULTS: First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Second, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8, a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality. CONCLUSIONS: These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs may ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8. We report the miRNA composition of 6-8 week old murine heart. We performed deep sequencing analysis to catalog the miRNA population in the adult heart. 2 sample were sequenced.

2011-10-11 | E-GEOD-32881 | biostudies-arrayexpress

Integrated small RNA, mRNA and protein omics reveal a miRNA network orchestrating metabolic maturation of the developing human heart

Project description:As the fetal heart develops, cardiomyocyte proliferation potential decreases while fatty acid oxidative capacity increases, a highly regulated transition known as cardiac maturation. Small noncoding RNAs, such as microRNAs (miRNAs), contribute to the establishment and control of tissue-specific transcriptional programs. However, small RNA expression dynamics and genome wide miRNA regulatory networks controlling maturation of the human fetal heart remain poorly understood. Transcriptome profiling of small RNAs revealed the temporal expression patterns of miRNA, piRNA, circRNA, snoRNA, snRNA and tRNA in the developing human heart between 8 and 19 weeks of gestation. Our analysis revealed that miRNAs were the most dynamically expressed small RNA species throughout mid-gestation. Cross-referencing differentially expressed miRNAs and mRNAs predicted 6,200 mRNA targets, 2134 of which were upregulated and 4066 downregulated as gestation progresses. Moreover, we found that downregulated targets of upregulated miRNAs predominantly control cell cycle progression, while upregulated targets of downregulated miRNAs are linked to energy sensing and oxidative metabolism. Furthermore, integration of miRNA and mRNA profiles with proteomes and reporter metabolites revealed that proteins encoded in mRNA targets, and their associated metabolites, mediate fatty acid oxidation and are enriched as the heart develops.This study revealed the small RNAome of the maturing human fetal heart. Furthermore, our findings suggest that coordinated activation and repression of miRNA expression throughout mid-gestation is essential to establish a dynamic miRNA-mRNA-protein network that decreases cardiomyocyte proliferation potential while increasing the oxidative capacity of the maturing human fetal heart.

2024-01-26 | PXD044936 | Pride

Functionally conserved non-coding regulators of cardiomyocyte proliferation and regeneration in mouse and human

Project description:The adult mammalian heart has little regenerative capacity after myocardial infarction (MI) while neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and non-coding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two thirds of each of the mRNAs, lncRNAs and microRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these microRNAs, miR-144-3p, miR-195a-5p, miR-451a and miR-6240 showed evidence of functional conservation in human cardiomyocytes. The sets of mRNAs, miRNAs and lncRNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.

2018-02-02 | E-MTAB-6272 | biostudies-arrayexpress

Dgcr8 function in the anterior second heart field

Project description:Morphogenesis of the heart is a complex process that relies on the precise gene expression and gene expression regulators during embryonic development. Dgcr8 is a gene involved in cardiac morphogenesis and it is in the chromosomal region deleted in 22q11.2DS patients. In order to study Dgcr8 function on heart development, we inactivated this gene in the cardiac progenitor cells of mouse embryos and did expression profiling of the long RNAs and miRNAs. We used microarrays to detail the global programme of gene expression downstream of DGCR8 underlying cardiac development.

2023-10-01 | GSE186064 | GEO

Circulating cardiac microRNA-FOXO3 axis safeguards against dilated cardiomyopathy

Project description:Background - Cardiac microRNAs (miRNAs) could be released into circulation thus becoming circulating cardiac miRNAs, which are increasingly recognized as noninvasive and readily accessible biomarker for multiple heart diseases. A global loss of cardiac miRNAs due to dicer or dgcr8 depletion has been reported to lead to dilated cardiomyopathy (DCM). However, DCM-associated circulating miRNAs (DACMs) and their roles in regulating DCM progression remain largely unexplored. Methods and Results - Through miRNA sequencing of human plasma procured from DCM patients and healthy control people, DCM was characterized with a unique expression pattern for circulating miRNAs. Among them, miR-26a-5p, miR-30c-5p, miR-126-5p, and miR-126-3p were all identified with dramatic reductions in DCM mouse myocardium as in the plasma of DCM patients. FOXO3, highlighted as a predicted common target gene, was experimentally demonstrated to be repressed within cardiomyocytes by these miRNAs except miR-26a-5p. Mechanistically, miRNA combination (miR-30c-5p, miR-126-5p, and miR-126-3p) significantly attenuated FOXO3-induced apoptosis and autophagy observed in cardiomyocytes as well as in DCM murine heart. Cardiac-specific knockout of FOXO3 conspicuously mitigated myocardial apoptosis and autophagy in DCM development. Moreover, stymieing the interaction between these miRNAs and FOXO3 mRNA extremely crippled the cardioprotection of these miRNAs against DCM progression. Cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and autophagy, thereby maintaining cardiac homeostasis and potently preventing DCM development. These findings may provide serological clues for the noninvasive diagnosis of DCM in the future, and unambiguously shed new light on DCM pathogenesis and associated therapeutic targets

2022-07-31 | GSE209991 | GEO

Genome wide transcript and miRNAanalysis of invitro and in-vivo generated human cardiac samples

Project description:We report the identification of miRNAs and transcripts that are regulated during human cardiac maturation. Examination of hESC-derived cardiomyocytes , human fetal tissue and human adult heart tissue for cardiomyocyte maturation.

2015-05-12 | E-GEOD-62913 | biostudies-arrayexpress

Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin; germline Parkin knockout mouse hearts.

Project description:Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood.We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes. 5 wild-type mouse hearts; 4 germline Parkin knockout mouse hearts Please note that the mouse cardiac examples were an adjunct to the Drosophila studies that comprised most of the associated publication. However, mRNA-sequencing was only performed on the mouse samples, not the Drosophila heart tubes.

2015-10-31 | E-GEOD-74517 | biostudies-arrayexpress

Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis

Project description:Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.

2022-03-03 | GSE168742 | GEO

MicroRNA profiling of the failing heart after myocardial infarction induction and doxorubicin treatment

Project description:The use of anthracycline antibiotics such as doxorubicin (DOX) has greatly improved the mortality and morbidity of cancer patients. However, the associated risk of cardiomyopathy has limited their clinical application. DOX-associated cardiotoxicity is irreversible and progresses to heart failure (HF). For this reason, a better understanding of the molecular mechanisms underlying these adverse cardiac effects is essential to develop improved regimes that include cardioprotective strategies. MicroRNAs (miRNAs) are short non-coding RNAs that are able to post-trascriptionally regulate gene expression. MiRNAs have been demonstrated to be involved in both cancer and cardiovascular disease. Therefore, we were interested in unveiling the potential role of miRNAs in chemotherapy-induced HF. We used a combination of three different models to recreate this cardiac toxicity (acute in vitro DOX treatment, DOX-induced HF in vivo and a myocardial infarction -MI- leading to failure model) to study the pattern of dysregulated miRNAs. Using RNA from all three conditions, miRNA microarray profiling was performed and a common miRNA signature was identified. Interestingly, these dysregulated miRNAs have been previously identified as involved in the failing heart. Our results suggest that DOX is able to alter the expression of miRNAs implicated in HF, in vitro as well as in vivo. The present study is a microRNA profiling of the damaged cardiac muscle (cardiomyocyte cell population), following either myocardial infarction (MI) induction or doxorubicin (DOX) treatment. Two DOX-treated models were included: ARC exposed to DOX in vitro and a validated DOX-induced heart failure model generated by repeated administration of DOX injections.

2013-01-29 | E-GEOD-36239 | biostudies-arrayexpress

Genome-wide analysis of gene expression changes in miR-214 KO mouse hearts and skeletal muscle

Project description:Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abrupt increases in intracellular Ca2+ during myocardial reperfusion cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Cardiac IR is accompanied by dynamic changes in expression of microRNAs (miRNAs), which inhibit specific mRNA targets. miR-214 is up-regulated during ischemic injury and heart failure in mice and humans, but its potential role in these processes is unknown. We show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury.

2012-01-31 | GSE35421 | GEO

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