Assessment of the Cardiac Noncoding Transcriptome by Single-Cell RNA Sequencing Identifies , a Conserved Profibrogenic Long Noncoding RNA.

Background: Cardiac fibroblasts have crucial roles in the heart. In particular, fibroblasts differentiate into myofibroblasts in the damaged myocardium, contributing to scar formation and interstitial fibrosis. Fibrosis is associated with heart dysfunction and failure.

A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification.

Aims: The major cardiac cell types composing the adult heart arise from common multipotent precursor cells. Cardiac lineage decisions are guided by extrinsic and cell-autonomous factors, including recently discovered long noncoding RNAs (lncRNAs). The human lncRNA CARMEN, which is known to dictate specification toward the cardiomyocyte (CM) and the smooth muscle cell (SMC) fates, generates a diversity of alternatively spliced isoforms.

Inhibition of the NOTCH1 Pathway in the Stressed Heart Limits Fibrosis and Promotes Recruitment of Non-Myocyte Cells into the Cardiomyocyte Fate.

Cardiac pathologies lead to an acute or gradual loss of cardiomyocytes. Because of the limited regenerative capacity of the mammalian heart, cardiomyocytes are only replaced by fibrotic tissue. Excessive fibrosis contributes to the deterioration of cardiac function and the transition to heart failure, which is the leading cause of morbidity and mortality worldwide.

ALDH1A3 Is the Key Isoform That Contributes to Aldehyde Dehydrogenase Activity and Affects Proliferation in Cardiac Atrial Appendage Progenitor Cells.

High aldehyde dehydrogenase (ALDH) activity has been reported in normal and cancer stem cells. We and others have shown previously that human ALDH cardiac atrial appendage cells are enriched with stem/progenitor cells. The role of ALDH in these cells is poorly understood but it may come down to the specific ALDH isoform(s) expressed.

A transcribed enhancer dictates mesendoderm specification in pluripotency.

Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors.

The long noncoding RNA controls cardiac fibrosis and remodeling.

Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified (Wisp2 super-enhancer-associated RNA) as a cardiac fibroblast-enriched lncRNA that regulates cardiac fibrosis after injury.

Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression.

The mechanisms controlling differentiation in adult cardiac precursor cells (CPCs) are still largely unknown. In this study, CPCs isolated from the human heart were found to produce predominantly smooth muscle cells but could be redirected to the cardiomyocyte fate by transient activation followed by inhibition of NOTCH signaling. NOTCH inhibition repressed expression, and blocked smooth muscle differentiation.

CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation.

The Notch pathway controls fibrotic and regenerative repair in the adult heart.

Aims: In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown.

β1-Integrin is up-regulated via Rac1-dependent reactive oxygen species as part of the hypertrophic cardiomyocyte response.

β(1)-Integrin mediates cardiomyocyte growth and survival and its proper regulation is essential for the structural and functional integrity of the heart. β(1)-Integrin expression is enhanced in hypertrophy, but the mechanism and significance of its up-regulation are unknown. Because reactive oxygen species (ROS) are important mediators of myocardial remodeling we examined their role in regulated β(1)-integrin expression.

Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.

Background: Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals.

The human urocortin 2 gene is regulated by hypoxia: identification of a hypoxia-responsive element in the 3'-flanking region.

Ucn2 (urocortin 2) has been shown to exert potent beneficial effects in the cardiovascular system, including inhibition of apoptosis, improvement of cardiomyocyte contractility and decrease of oxidative stress. The mechanisms that contribute to the regulation of hUcn2 (human Ucn2) expression in cardiovascular pathologies are not known. In the present study, we analysed the mechanism by which hypoxia, a major stimulus in ischaemic heart disease, regulates Ucn2 gene expression.

RhoA GTPase and F-actin dynamically regulate the permeability of Cx43-made channels in rat cardiac myocytes.

Gap junctions are clusters of transmembrane channels allowing a passive diffusion of ions and small molecules between adjacent cells. Connexin43, the main channel-forming protein expressed in ventricular myocytes, can associate with zonula occludens-1, a scaffolding protein linked to the actin cytoskeleton and to signal transduction molecules. The possible influence of Rho GTPases, major regulators of cellular junctions and of the actin cytoskeleton, in the modulation of gap junctional intercellular communication (GJIC) was examined.

TNF-alpha increases protein content in C2C12 and primary myotubes by enhancing protein translation via the TNF-R1, PI3K, and MEK.

Recent evidence supports that TNF-alpha, long considered a catabolic factor, may also have a physiological function in skeletal muscle. The catabolic view, mainly based on correlative studies in human and in vivo animal models, was challenged by experiments with myoblasts, in which TNF-alpha induced differentiation. The biological effects of TNF-alpha in differentiated muscle, however, remain poorly understood.

Is the junctional uncoupling elicited in rat ventricular myocytes by some dephosphorylation treatments due to changes in the phosphorylation status of Cx43?

Gap junctions, specialized membrane structures that mediate cell-to-cell communication in almost all animal tissues, are composed of channel-forming integral membrane proteins termed connexins. Most of them, particularly connexin43 (Cx43), the most ubiquitous connexin, the major connexin present in cardiac myocytes, are phosphoproteins. Connexin phosphorylation has been thought to regulate gap junctional protein trafficking, gap junction assembly, channel gating, and turnover.

The metabolic inhibitor antimycin A can disrupt cell-to-cell communication by an ATP- and Ca(2+)-independent mechanism.

In cardiac myocytes of new-born rats, the degree of intercellular communication through gap junctional channels closely depends on the metabolic state of the cells. In contrast, in stably transfected HeLa cells expressing rat cardiac connexin43 (Cx43, the main channel-forming protein present in ventricular myocytes), a major part of junctional communication persisted in ATP-depleted conditions, in the presence of a metabolic inhibitor (KCN) or of a broad spectrum inhibitor of protein kinases (H7). However, another metabolic inhibitor, antimycin A, which like cyanide inhibits electron transfer in the respiratory chain, totally interrupted cell-to-cell communication between Cx43-HeLa cells, even in whole-cell conditions, when ATP (5 mM) was present.