• congenital heart defect
• maternal diabetes
• microRNA
• mitochondrial fusion
• mitofusin 1
• mitofusin 2

• R01 HL153141 NHLBI NIH HHS
• R01 DK101972 NIDDK NIH HHS
• R01 HL131737 NHLBI NIH HHS
• R01 DK103024 NIDDK NIH HHS
• R01 HL139060 NHLBI NIH HHS
• R01 DK083243 NIDDK NIH HHS
• R01 HL151108 NHLBI NIH HHS
• R01 GM129584 NIGMS NIH HHS
• R01 HL134368 NHLBI NIH HHS

• Cardiac maturation
• Cell cycle progression
• Energy homeostasis
• Human fetal heart development
• Metabolic maturation
• Proteomics
• Small non-coding RNA
• Transcriptional regulatory networks
• Transcriptomics
• microRNA

• Humans
• RNA, Messenger/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Gene Expression Profiling
• Fatty Acids

• cardiomyocyte metabolism
• disease modelling
• heart microtissues
• heart organogenesis
• human pluripotent stem cells
• maturation

Human heart development is a complex and tightly regulated process, conserving proliferation, and multipotency of embryonic cardiovascular progenitors. At terminal stage, progenitor cell type gets suppressed for terminal differentiation and maturation. In the human heart, most cardiomyocytes are terminally differentiated and so have limited proliferation capacity. MicroRNAs (miRNAs) are non-coding single-stranded RNA that regulate gene expression and mRNA silencing at the post-transcriptional level. These miRNAs play a crucial role in numerous biological events, including cardiac development, and cardiomyocyte proliferation. Several cardiac cells specific miRNAs have been discovered. Inhibition or overexpression of these miRNAs could induce cardiac regeneration, cardiac stem cell proliferation and cardiomyocyte proliferation. Clinical application of miRNAs extends to heart failure, wherein the cell cycle arrest of terminally differentiated cardiac cells inhibits the heart regeneration. The regenerative capacity of the myocardium can be enhanced by cardiomyocyte specific miRNAs controlling the cell cycle. In this review, we focus on cardiac-specific miRNAs involved in cardiac regeneration and cardiomyocyte proliferation, and their potential as a new clinical therapy for heart regeneration.

• Fetal sex
• Gene regulation
• Placenta
• Small RNA
• miRNA

• Animals
• Brain/embryology
• Brain/metabolism
• Female
• Mice
• MicroRNAs/metabolism
• Placenta/metabolism
• Pregnancy
• Sex Characteristics

Heart development requires robust gene regulation, and the related disruption could lead to congenital heart disease (CHD). To gain insights into the regulation of gene expression in CHD, we obtained the expression profiles of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in 22 heart tissue samples with tetralogy of Fallot (TOF) through strand-specific transcriptomic analysis. Using a causal inference framework based on the expression correlations and validated microRNA (miRNA)–lncRNA–mRNA evidences, we constructed the competing endogenous RNA (ceRNA)-mediated network driven by lncRNAs. Four lncRNAs (FGD5-AS1, lnc-GNB4-1, lnc-PDK3-1, and lnc-SAMD5-1) were identified as hub lncRNAs in the network. FGD5-AS1 was selected for further study since all its targets were CHD-related genes (NRAS, PTEN, and SMAD4). Both FGD5-AS1 and SMAD4 could bind with hsa-miR-421, which has been validated using dual-luciferase reporter assays. Knockdown of FGD5-AS1 not only significantly reduced PTEN and SMAD4 expression in HEK 293 and the fetal heart cell line (CCC-HEH-2) but also increased the transcription of its interacted miRNAs in a cell-specific way. Besides ceRNA mechanism, RNAseq and ATACseq results showed that FGD5-AS1 might play repression roles in heart development by transcriptionally regulating CHD-related genes. In conclusion, we identified a ceRNA network driven by lncRNAs in heart tissues of TOF patients. Furthermore, we proved that FGD5-AS1, one hub lncRNA in the TOF heart ceRNA network, regulates multiple genes transcriptionally and epigenetically.

• FGD5-AS1
• congenital heart disease
• gene expression
• lncRNA
• tetralogy of Fallot

• H-type blood vessel
• bone dysplasia
• connective tissue growth factor
• microRNA375
• prenatal caffeine exposure

• Apoptosis
• Autofagia
• Autophagy
• Biomarcadores
• Biomarkers
• Células cardiacas humanas
• Endoplasmic reticulum stress
• Estrés del retículo endoplasmático
• Human cardiac cells
• Ischemic dilated cardiomyopathy
• Miocardiopatía dilatada isquémica
• miR-16

• IRS1
• PRL
• dairy cows
• miR-183
• milk fat metabolism

• Animals
• Cattle
• Cells, Cultured
• DNA Methylation
• Down-Regulation
• Epigenesis, Genetic
• Epithelial Cells/cytology
• Epithelial Cells/metabolism
• Female
• Insulin Receptor Substrate Proteins/genetics
• Lipid Metabolism
• Mammary Glands, Animal/cytology
• Mammary Glands, Animal/metabolism
• MicroRNAs/genetics
• Milk/metabolism
• Prolactin/genetics
• Signal Transduction

• Exosomes
• Foetal diseases
• MicroRNAs
• Pregnancy complications
• Pregnant women

Development of the complex human heart is tightly regulated at multiple levels, maintaining multipotency and proliferative state in the embryonic cardiovascular progenitors and thereafter suppressing progenitor characteristics to allow for terminal differentiation and maturation. Small regulatory microRNAs (miRNAs) are at the level of post-transcriptional gene suppressors, which enhance the degradation or decay of their target protein-coding mRNAs. These miRNAs are known to play roles in a large number of biological events, cardiovascular development being no exception. A number of critical cardiac-specific miRNAs have been identified, of which structural developmental defects have been linked to dysregulation of miRNAs in the proliferating cardiac stem cells. These miRNAs present in the stem cell niche are lost when the cardiac progenitors terminally differentiate, resulting in the postnatal mitotic arrest of the heart. Therapeutic applications of these miRNAs extend to the realm of heart failure, whereby the death of heart cells in the ageing heart cannot be replaced due to the arrest of cell division. By utilizing miRNA therapy to control cell cycling, the regenerative potential of matured myocardium can be restored. This review will address the various cardiac progenitor-related miRNAs that control the development and proliferative potential of the heart.

• Cardiac development
• Cardiac regeneration and development
• Cardiovascular progenitors
• MicroRNA
• Stem cell niche

• Atrial fibrillation
• PITX2
• SNPs
• hypertension
• hyperthyroidism
• non-coding RNAs.

• Animals
• Atrial Fibrillation/genetics
• Gene Expression Regulation
• Gene Regulatory Networks
• Homeodomain Proteins/genetics
• Humans
• Polymorphism, Single Nucleotide
• Transcription Factors/genetics
• Homeobox Protein PITX2

• Bioinformatics
• Chicken heart development
• Fetal cardiac miRNA
• Gene re-programming

MiRNAs are a class of endogenous, short, single-stranded, non-coding RNAs, which are tightly linked to cardiac disorders such as myocardial ischemia/reperfusion (I/R) injury. MiR-34a is known to be involved in the hypoxia-induced cardiomyocytes apoptosis. However, the molecular mechanisms are unclear. In the present study, we demonstrate that under low glucose supply, rat cardiomyocytes are susceptible to hypoxia. Under short-time hypoxia, cellular glucose uptake and lactate product are induced but under long-time hypoxia, the cellular glucose metabolism is suppressed. Interestingly, an adaptive up-regulation of miR-34a by long-time hypoxia was observed both in vitro and in vivo, leading to suppression of glycolysis in cardiomyocytes. We identified lactate dehydrogenase-A (LDHA) as a direct target of miR-34a, which binds to the 3′-UTR region of LDHA mRNA in cardiomyocytes. Moreover, inhibition of miR-34a attenuated hypoxia-induced cardiomyocytes dysfunction through restoration of glycolysis. The present study illustrates roles of miR-34a in the hypoxia-induced cardiomyocytes dysfunction and proposes restoration of glycolysis of dysfunctional cardiomyocytes by inhibiting miR-34a during I/R might be an effectively therapeutic approach against I/R injury.

• LDHA
• cardiomyocytes dysfunction
• glycolysis
• hypoxic stress
• miR-34a

Sepsis is an inflammatory response to pathogens (such as Gram-positive and Gram-negative bacteria), which has high morbidity and mortality in critically ill patients. The present study aimed to identify the key genes in Gram-positive and Gram-negative sepsis. GSE6535 was downloaded from Gene Expression Omnibus, containing 17 control samples, 18 Gram-positive samples and 25 Gram-negative samples. Subsequently, the limma package in R was used to screen the differentially expressed genes (DEGs). Hierarchical clustering was conducted for the specific DEGs in Gram-negative and Gram-negative samples using cluster software and the TreeView software. To analyze the correlation of samples at the gene level, a similarity network was constructed using Cytoscape software. Functional and pathway enrichment analyses were conducted for the DEGs using DAVID. Finally, stochastic perturbation was used to determine the significantly differential functions between Gram-positive and Gram-negative samples. A total of 340 and 485 DEGs were obtained in Gram-positive and Gram-negative samples, respectively. Hierarchical clustering revealed that there were significant differences between control and sepsis samples. In Gram-positive and Gram-negative samples, myeloid cell leukemia sequence 1 was associated with apoptosis and programmed cell death. Additionally, NADH:ubiquinone oxidoreductase subunit S4 was associated with mitochondrial respiratory chain complex I assembly. Stochastic perturbation analysis revealed that NADH:ubiquinone oxidoreductase subunit B2 (NDUFB2), NDUFB8 and ubiquinol-cytochrome c reductase hinge protein (UQCRH) were associated with cellular respiration in Gram-negative samples, whereas large tumor suppressor kinase 2 (LATS2) was associated with G1/S transition of the mitotic cell cycle in Gram-positive samples. NDUFB2, NDUFB8 and UQCRH may be biomarkers for Gram-negative sepsis, whereas LATS2 may be a biomarker for Gram-positive sepsis. These findings may promote the therapies of sepsis caused by Gram-positive and Gram-negative bacteria.

Atrial fibrillation (AF) is the most frequent arrhythmogenic syndrome in humans. With an estimate incidence of 1%-2% in the general population, AF raises up to almost 10%-12% in 80+ years. Thus, AF represents nowadays a highly prevalent medical problem generating a large economic burden. At the electrophysiological level, distinct mechanisms have been elucidated. Yet, despite its prevalence, the genetic and molecular culprits of this pandemic cardiac electrophysiological abnormality have remained largely obscure. Molecular genetics of AF familiar cases have demonstrated that single nucleotide mutations in distinct genes encoding for ion channels underlie the onset of AF, albeit such alterations only explain a minor subset of patients with AF. In recent years, analyses by means of genome-wide association studies have unraveled a more complex picture of the etiology of AF, pointing out to distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Furthermore a new layer of regulatory mechanisms have emerged, i.e., post-transcriptional regulation mediated by non-coding RNA, which have been demonstrated to exert pivotal roles in cardiac electrophysiology. In this manuscript, we aim to provide a comprehensive review of the genetic regulatory networks that if impaired exert electrophysiological abnormalities that contribute to the onset, and subsequently, on self-perpetuation of AF.

• Atrial fibrillation
• Genetics
• MicroRNAs
• Genome-wide association studies
• PITX2

• EMT
• cardiac valve development
• miR-199a
• miR-23b