HDncRNA: a comprehensive database of non-coding RNAs associated with heart diseases.

Heart diseases (HDs) represent a common group of diseases that involve the heart, a number of which are characterized by high morbidity and lethality. Recently, increasing evidence demonstrates diverse non-coding RNAs (ncRNAs) play critical roles in HDs. However, currently there lacks a systematic investigation of the association between HDs and ncRNAs. Here, we developed a Heart Disease-related Non-coding RNAs Database (HDncRNA), to curate the HDs-ncRNA associations from 3 different sources including 1904 published articles, 3 existing databases [the Human microRNA Disease Database (HMDD), miR2disease and lncRNAdisease] and 5 RNA-seq datasets. The HDs-ncRNA associations with experimental validations curated from these articles, HMDD, miR2disease and part of data from lncRNAdisease were 'direct evidence'. Relationships got from high-through data in lncRNAdisease and annotated differential expressed lncRNAs from RNA-seq data were defined as 'high-throughput associations'. Novel lncRNAs identified from RNA-seq data in HDs had least credibility and were defined as 'predicted associations'. Currently, the database contains 2304 HDs-ncRNA associations for 133 HDs in 6 species including human, mouse, rat, pig, calf and dog. The database also has the following features: (i) A user-friendly web interface for browsing and searching the data; (ii) a visualization tool to plot miRNA and lncRNA locations in the human and mouse genomes; (iii) information about neighboring genes of lncRNAs and (iv) links to some mainstream databases including miRbase, Ensemble and Fantom Cat for the annotated lncRNAs and miRNAs. In summary, HDncRNA provides an excellent platform for exploring HDs related ncRNAs.Database URL: http://hdncrna.cardiacdev.com.

miR-218 Involvement in Cardiomyocyte Hypertrophy Is Likely through Targeting REST.

MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with significant risks of heart failure. However, many microRNAs are still not recognized for their functions in pathophysiological processes. In this study, we evaluated effects of miR-218 in cardiomyocyte hypertrophy using both in vitro and in vivo models. We found that miR-218 was evidently downregulated in a transverse aortic constriction (TAC) mouse model. Overexpression of miR-218 is sufficient to reduce hypertrophy, whereas the suppression of miR-218 aggravates hypertrophy in primary cardiomyocytes induced by isoprenaline (ISO). In addition, we identified RE1-silencing transcription factor (REST) as a novel target of miR-218; it negatively regulated the expression of REST in hypertrophic cardiomyocytes and the TAC model. These results showed that miR-218 plays a crucial role in cardiomyocyte hypertrophy, likely via targeting REST, suggesting a potential candidate target for interfering hypertrophy.

PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome.

Congenital heart disease (CHD), the most common type of birth defect, is still the leading non-infectious cause of infant morbidity and mortality in humans. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic components underpinning CHD in an overwhelming majority of patients remain unclear. In the present study, the coding exons and flanking introns of the PITX2 gene, which encodes a paired-like homeodomain transcription factor 2essential for cardiovascular morphogenesis as well as maxillary facial development, was sequenced in 196 unrelated patients with CHD and subsequently in the mutation carrier's family members available. As a result, a novel heterozygous PITX2 mutation, p.Q102X for PITX2a, or p.Q148X for PITX2b, or p.Q155X for PITX2c, was identified in a family with endocardial cushion defect (ECD) and Axenfeld-Rieger syndrome (ARS). Genetic analysis of the pedigree showed that the nonsense mutation co-segregated with ECD and ARS transmitted in an autosomal dominant pattern with complete penetrance. The mutation was absent in 800 control chromosomes from an ethnically matched population. Functional analysis by using a dual-luciferase reporter assay system revealed that the mutant PITX2 had no transcriptional activity and that the mutation eliminated synergistic transcriptional activation between PITX2 and NKX2.5, another transcription factor pivotal for cardiogenesis. To our knowledge, this is the first report on the association of PITX2 loss-of-function mutation with increased susceptibility to ECD and ARS. The findings provide novel insight into the molecular mechanisms underpinning ECD and ARS, suggesting the potential implications for the antenatal prophylaxis and personalized treatment of CHD and ARS.

GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy.

The cardiac transcription factor GATA4 is essential for cardiac development, and mutations in this gene have been implicated in a wide variety of congenital heart diseases in both animal models and humans. However, whether mutated GATA4 predisposes to dilated cardiomyopathy (DCM) remains unknown. In this study, the whole coding region and splice junction sites of the GATA4 gene was sequenced in 110 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.C271S, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis demonstrated that the GATA4 mutant was associated with significantly decreased transcriptional activity and remarkably reduced synergistic activation between GATA4 and NKX2-5, another transcription factor crucial for cardiogenesis. The findings provide novel insight into the molecular mechanisms involved in the pathogenesis of DCM, suggesting the potential implications in the prenatal diagnosis and gene-specific treatment for this common form of myocardial disorder.

Dynamin-2 mediates heart failure by modulating Ca2+ -dependent cardiomyocyte apoptosis.

BACKGROUND: Heart failure (HF) is approaching an epidemic proportion and has become one of the leading causes of death. It imposes a great burden on the healthcare system and society. Remodeling of cardiomyocyte membranes has a profound role in the pathogenesis of HF. However, whether dynamin (DNM), a membrane-remodeling GTPase, is associated with HF remains unclear. METHODS AND RESULTS: Here, we identified that DNM2 is necessary for the maintenance of cardiac function. Endogenous DNM2 protein levels were gradually decreased in parallel with the progression of HF in different experimental animal models. Decreased DNM2 level was also observed in the end-stage failing human heart. DNM2-deficient zebrafish exhibited signs of notable cardiac apoptosis and eventually developed severe HF. Mechanistic study showed that DNM2 downregulation caused cardiomyocyte sarcoplasmic reticulum Ca(2+) overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca(2+) channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca(2+)-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF. CONCLUSIONS: DNM2 mediates HF by modulating Ca(2+)-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment.

MicroRNA-134 as a potential plasma biomarker for the diagnosis of acute pulmonary embolism.

BACKGROUND: Acute pulmonary embolism (APE) remains a diagnostic challenge due to a variable clinical presentation and the lack of a reliable screening tool. MicroRNAs (miRNAs) regulate gene expression in a wide range of pathophysiologic processes. Circulating miRNAs are emerging biomarkers in heart failure, type 2 diabetes and other disease states; however, using plasma miRNAs as biomarkers for the diagnosis of APE is still unknown. METHODS: Thirty-two APE patients, 32 healthy controls, and 22 non-APE patients (reported dyspnea, chest pain, or cough) were enrolled in this study. The TaqMan miRNA microarray was used to identify dysregulated miRNAs in the plasma of APE patients. The TaqMan-based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate the dysregulated miRNAs. The receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the miRNA identified as the candidate biomarker. RESULTS: Plasma miRNA-134 (miR-134) level was significantly higher in the APE patients than in the healthy controls or non-APE patients. The ROC curve showed that plasma miR-134 was a specific diagnostic predictor of APE with an area under the curve of 0.833 (95% confidence interval, 0.737 to 0.929; P < 0.001). CONCLUSIONS: Our findings indicated that plasma miR-134 could be an important biomarker for the diagnosis of APE. Because of this finding, large-scale investigations are urgently needed to pave the way from basic research to clinical utilization.