scholarly journals Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration

2007 ◽  
Vol 87 (2) ◽  
pp. 521-544 ◽  
Author(s):  
Preeti Ahuja ◽  
Patima Sdek ◽  
W. Robb MacLellan
Keyword(s):  
Cell Cycle ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Cell Cycle Control ◽  
Cardiac Regeneration ◽  
Perinatal Period ◽  
Fetal Life ◽  
Cell Cycle Reentry ◽  
Adult Cardiac Myocytes ◽  
Species Specific

Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle soon after birth in mammals. Although the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and species-specific differences may exist, it appears that for the vast majority of adult cardiac myocytes the predominant form of growth postnatally is an increase in cell size (hypertrophy) not number. Unfortunately, this limits the ability of the heart to restore function after any significant injury. Interest in novel regenerative therapies has led to the accumulation of much information on the mechanisms that regulate the rapid proliferation of cardiac myocytes in utero, their cell cycle exit in the perinatal period, and the permanent arrest (terminal differentiation) in adult myocytes. The recent identification of cardiac progenitor cells capable of giving rise to cardiac myocyte-like cells has challenged the dogma that the heart is a terminally differentiated organ and opened new prospects for cardiac regeneration. In this review, we summarize the current understanding of cardiomyocyte cell cycle control in normal development and disease. In addition, we also discuss the potential usefulness of cardiomyocyte self-renewal as well as feasibility of therapeutic manipulation of the cardiac myocyte cell cycle for cardiac regeneration.

Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart

2007 ◽  
Vol 102 (3) ◽  
pp. 1130-1142 ◽  
Author(s):  
Sonnet S. Jonker ◽  
Lubo Zhang ◽  
Samantha Louey ◽  
George D. Giraud ◽  
Kent L. Thornburg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Terminal Differentiation ◽  
Normal Growth ◽  
Mass Gain ◽  
Perinatal Period ◽  
Cross Sectional ◽  
Fetal Sheep ◽  
Cardiac Growth

The generation of new myocytes is an essential process of in utero heart growth. Most, or all, cardiac myocytes lose their capacity for proliferation during the perinatal period through the process of terminal differentiation. An increasing number of studies focus on how experimental interventions affect cardiac myocyte growth in the fetal sheep. Nevertheless, fundamental questions about normal growth of the fetal heart remain unanswered. In this study, we determined that during the last third of gestation the hearts of fetal sheep grew primarily by four processes. 1) Myocyte proliferation contributed substantially to daily cardiac mass gain, and the number of cardiac myocytes continued to increase to term. 2) The (hitherto unrecognized) contribution to cardiac growth by the increase in myocyte size associated with the transition from mononucleation to binucleation (terminal differentiation) became considerable from ∼115 days of gestational age (dGA) until term (145dGA). Because binucleation became the more frequent outcome of myocyte cell cycle activity after ∼115dGA, the number of binucleated myocytes increased at the expense of the number of mononucleated myocytes. Both the interval between nuclear divisions and the duration of cell cycle activity in myocytes decreased substantially during this same period. Finally, cardiac growth was in part due to enlargement of 3) mononucleated and 4) binucleated myocytes, which grew in cross-sectional diameter but not length during the last third of gestation. These data on normal cardiac growth may enable a more detailed understanding of the consequences of experimental and pathological interventions in prenatal life.

scholarly journals Hypoxia-induced myocardial regeneration

2017 ◽  
Vol 123 (6) ◽  
pp. 1676-1681 ◽  
Author(s):  
Wataru Kimura ◽  
Yuji Nakada ◽  
Hesham A. Sadek
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Systolic Heart Failure ◽  
Cardiac Regeneration ◽  
Oxygen Metabolism ◽  
Functional Improvement ◽  
Cardiomyocyte Proliferation ◽  
Mammalian Heart ◽  
Cell Cycle Reentry ◽  
And Oxidative Stress

The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration.

Cell-cell contact between adult rat cardiac myocytes regulates Kv1.5 and Kv4.2 K+channel mRNA expression

1998 ◽  
Vol 275 (6) ◽  
pp. C1473-C1480 ◽  
Author(s):  
Kenneth M. Hershman ◽  
Edwin S. Levitan
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Cardiac Myocytes ◽  
Cell Density ◽  
Cardiac Myocyte ◽  
Live Cells ◽  
K Channel ◽  
Cell Contact ◽  
Adult Cardiac Myocytes ◽  
Cell Cell

Regulation of voltage-gated K+channel genes represents an important mechanism for modulating cardiac excitability. Here we demonstrate that expression of two K+channel mRNAs is reciprocally controlled by cell-cell interactions between adult cardiac myocytes. It is shown that culturing acutely dissociated rat ventricular myocytes for 3 h results in a dramatic downregulation of Kv1.5 mRNA and a modest upregulation of Kv4.2 mRNA. These effects are specific, because similar changes are not detected with other channel mRNAs. Increasing myocyte density promotes maintenance of Kv1.5 gene expression, whereas Kv4.2 mRNA expression was found to be inversely proportional to cell density. Conditioned culture medium did not mimic the effects of high cell density. However, paraformaldehyde-fixed myocytes were comparable to live cells in their ability to influence K+channel message levels. Thus the reciprocal effects of cell density on the expression of Kv1.5 and Kv4.2 genes are mediated by direct contact between adult cardiac myocytes. These findings reveal for the first time that cardiac myocyte gene expression is influenced by signaling induced by cell-cell contact.

scholarly journals Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity

2021 ◽  
Vol 118 (12) ◽  
pp. e2011876118
Author(s):  
Stefania Ippati ◽  
Yuanyuan Deng ◽  
Julia van der Hoven ◽  
Celine Heu ◽  
Annika van Hummel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Dynamic Process ◽  
Cell Cycle Control ◽  
Amyloid Β ◽  
Current View ◽  
Cell Cycle Reentry ◽  
Reporter Signal ◽  
Control Protein ◽  
Cycle Indicator

Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer’s disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-β (oAβ) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAβ challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aβ precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aβ toxicity.

scholarly journals Cell cycle control during early embryogenesis

Development ◽  
2021 ◽  
Vol 148 (13) ◽  
Author(s):  
Susanna E. Brantley ◽  
Stefano Di Talia
Keyword(s):  
Cell Cycle ◽  
Quantitative Imaging ◽  
Cell Cycle Control ◽  
Embryonic Cell ◽  
Early Embryogenesis ◽  
Model Systems ◽  
Drosophila Embryo ◽  
Cell Cycles ◽  
Physical Mechanisms ◽  
Species Specific

ABSTRACT Understanding the mechanisms of embryonic cell cycles is a central goal of developmental biology, as the regulation of the cell cycle must be closely coordinated with other events during early embryogenesis. Quantitative imaging approaches have recently begun to reveal how the cell cycle oscillator is controlled in space and time, and how it is integrated with mechanical signals to drive morphogenesis. Here, we discuss how the Drosophila embryo has served as an excellent model for addressing the molecular and physical mechanisms of embryonic cell cycles, with comparisons to other model systems to highlight conserved and species-specific mechanisms. We describe how the rapid cleavage divisions characteristic of most metazoan embryos require chemical waves and cytoplasmic flows to coordinate morphogenesis across the large expanse of the embryo. We also outline how, in the late cleavage divisions, the cell cycle is inter-regulated with the activation of gene expression to ensure a reliable maternal-to-zygotic transition. Finally, we discuss how precise transcriptional regulation of the timing of mitosis ensures that tissue morphogenesis and cell proliferation are tightly controlled during gastrulation.

Abstract P193: Nuclear Localization of the α1B-Adrenergic Receptor Subtype Is Required for Hypertrophic Signaling in Cardiac Myocytes

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Steven C Wu ◽  
Andrew L Cypher ◽  
Chastity L Healy ◽  
Casey D Wright ◽  
Yuan Huang ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Nuclear Localization ◽  
Adrenergic Receptors ◽  
Cardiac Myocyte ◽  
Nuclear Localization Sequence ◽  
Gene Marker ◽  
Receptor Subtype ◽  
Wild Type ◽  
Adult Cardiac Myocytes ◽  
Hypertrophic Signaling

We previously demonstrated that α1-adrenergic receptors (α1-ARs) in the heart are required for physiologic hypertrophy during development and prevent a maladaptive response to pathologic stress. We have also shown that the major subtypes, α1A and α1B, both localize to the nucleus in adult cardiac myocytes. Importantly, we have defined a nuclear α1A-ERK survival and an α1A-PKCδ-cTnI inotropic signaling pathway that both originate at the nucleus and are transduced to cytosolic targets, suggesting that the α1A is required for cardiac myocyte survival and contractility. However, less is known about the molecular function of the α1B. In the current study, we examined the role of the α1B-subtype in hypertrophic signaling. First, we identified a bi-partite nuclear localization sequence (NLS) in the carboxy-terminal tail of the receptor. Mutation of the NLS (α1B-NLSmut) disrupted its localization to the nucleus when expressed in adult cardiac myocytes. We then compared hypertrophic signaling of the wild-type α1B- to the mutated receptor by reconstitution in cardiac myocytes lacking endogenous α1B (α1BKO) receptors. Activation of the wild-type receptor by the α1-agonist phenylephrine in α1BKO myocytes restored hypertrophic signaling, as we observed increased phosphorylation of protein kinase C (PKC) isoforms δ and ε, and histone deacetylases (HDAC) 4 and 5. We also observed increased expression of the hypertrophic gene marker, atrial natriuretic factor (ANF). Expression of the α1B-NLSmut failed to activate hypertrophic signaling in α1BKO cardiac myocytes despite phenylephrine stimulation. Together, our data show that nuclear localization of the α1B-subtype is required for hypertrophic signaling and overall further suggest that α1-adrenergic receptors are functional only at the nucleus in cardiac myocytes.

scholarly journals FGF-16 is released from neonatal cardiac myocytes and alters growth-related signaling: a possible role in postnatal development

2008 ◽  
Vol 294 (5) ◽  
pp. C1242-C1249 ◽  
Author(s):  
Shun Yan Lu ◽  
David P. Sontag ◽  
Karen A. Detillieux ◽  
Peter A. Cattini
Keyword(s):  
Cell Cycle ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Gene Array ◽  
Neonatal Rat ◽  
Proliferative Potential ◽  
Mrna Accumulation ◽  
Fgf Receptor ◽  
Adult Rat ◽  
Pkc Activation

FGF-16 has been reported to be preferentially expressed in the adult rat heart. We have investigated the expression of FGF-16 in the perinatal and postnatal heart and its functional significance in neonatal rat cardiac myocytes. FGF-16 mRNA accumulation was observed by quantitative RT-PCR between neonatal days 1 and 7, with this increased expression persisting into adulthood. FGF-2 has been shown to increase neonatal rat cardiac myocyte proliferative potential via PKC activation. Gene array analysis revealed that FGF-16 inhibited the upregulation by FGF-2 of cell cycle promoting genes including cyclin F and Ki67. Furthermore, the CDK4/6 inhibitor gene Arf/INK4A was upregulated with the combination of FGF-16 and FGF-2 but not with either factor on its own. The effect on Ki67 was validated by protein immunodetection, which also showed that FGF-16 significantly decreased FGF-2-induced Ki67 labeling of cardiac myocytes, although it alone had no effect on Ki67 labeling. Inhibition of p38 MAPK potentiated cardiac myocyte proliferation induced by FGF-2 but did not alter the inhibitory action of FGF-16. Receptor binding assay showed that FGF-16 can compete with FGF-2 for binding sites including FGF receptor 1. FGF-16 had no effect on activated p38, ERK1/2, or JNK/SAPK after FGF-2 treatment. However, FGF-16 inhibited PKC-α and PKC-ε activation induced by FGF-2 and, importantly, IGF-1. Collectively, these data suggest that expression and release of FGF-16 in the neonatal myocardium interfere with cardiac myocyte proliferative potential by altering the local signaling environment via modulation of PKC activation and cell cycle-related gene expression.

Parvalbumin isoforms differentially accelerate cardiac myocyte relaxation kinetics in an animal model of diastolic dysfunction

2007 ◽  
Vol 293 (3) ◽  
pp. H1705-H1713 ◽  
Author(s):  
David W. Rodenbaugh ◽  
Wang Wang ◽  
Jennifer Davis ◽  
Terri Edwards ◽  
James D. Potter ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Adenoviral Vectors ◽  
Cation Binding ◽  
Mechanical Relaxation ◽  
Binding Affinities ◽  
Naturally Occurring ◽  
Adult Cardiac Myocytes ◽  
Cardiac Relaxation

The cytosolic Ca2+/Mg2+-binding protein α-parvalbumin (α-Parv) has been shown to accelerate cardiac relaxation; however, beyond an optimal concentration range, α-Parv can also diminish contractility. Mathematical modeling suggests that increasing Parv's Mg2+ affinity may lower the effective concentration of Parv ([Parv]) to speed relaxation and, thus, limit Parv-mediated depressed contraction. Naturally occurring α/β-Parv isoforms show divergence in amino acid primary structure (57% homology) and cation-binding affinities, with β-Parv having an estimated 16% greater Mg2+ affinity and ∼200% greater Ca2+ affinity than α-Parv. We tested the hypothesis that, at the same or lower estimated [Parv], mechanical relaxation rate would be more significantly accelerated by β-Parv than by α-Parv. Dahl salt-sensitive (DS) rats were used as an experimental model of diastolic dysfunction. Relaxation properties were significantly slowed in adult cardiac myocytes isolated from DS rats compared with controls: time from peak contraction to 50% relaxation was 57 ± 2 vs. 49 ± 2 (SE) ms ( P < 0.05), validating this model system. DS cardiac myocytes were subsequently transduced with α- or β-Parv adenoviral vectors. Upon Parv gene transfer, β-Parv caused significantly faster relaxation than α-Parv ( P < 0.05), even though estimated [β-Parv] was ∼10% of [α-Parv]. This comparative analysis showing distinct functional outcomes raises the prospect of utilizing naturally occurring Parv variants to address disease-associated slowed cardiac relaxation.

scholarly journals Cardiac myocyte exosomes: stability, HSP60, and proteomics

2013 ◽  
Vol 304 (7) ◽  
pp. H954-H965 ◽  
Author(s):  
Z. A. Malik ◽  
K. S. Kott ◽  
A. J. Poe ◽  
T. Kuo ◽  
L. Chen ◽  
...  
Keyword(s):  
Protein Content ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Lipid Vesicles ◽  
Underlying Mechanism ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Viral Particles ◽  
Adult Cardiac Myocytes ◽  
Cardiac Myocyte Apoptosis

Exosomes, which are 50- to 100-nm-diameter lipid vesicles, have been implicated in intercellular communication, including transmitting malignancy, and as a way for viral particles to evade detection while spreading to new cells. Previously, we demonstrated that adult cardiac myocytes release heat shock protein (HSP)60 in exosomes. Extracellular HSP60, when not in exosomes, causes cardiac myocyte apoptosis via the activation of Toll-like receptor 4. Thus, release of HSP60 from exosomes would be damaging to the surrounding cardiac myocytes. We hypothesized that 1) pathological changes in the environment, such as fever, change in pH, or ethanol consumption, would increase exosome permeability; 2) different exosome inducers would result in different exosomal protein content; 3) ethanol at “physiological” concentrations would cause exosome release; and 4) ROS production is an underlying mechanism of increased exosome production. We found the following: first, exosomes retained their protein cargo under different physiological/pathological conditions, based on Western blot analyses. Second, mass spectrometry demonstrated that the protein content of cardiac exosomes differed significantly from other types of exosomes in the literature and contained cytosolic, sarcomeric, and mitochondrial proteins. Third, ethanol did not affect exosome stability but greatly increased the production of exosomes by cardiac myocytes. Fourth, ethanol- and hypoxia/reoxygenation-derived exosomes had different protein content. Finally, ROS inhibition reduced exosome production but did not completely inhibit it. In conclusion, exosomal protein content is influenced by the cell source and stimulus for exosome formation. ROS stimulate exosome production. The functions of exosomes remain to be fully elucidated.

β-Adrenergic- and muscarinic receptor-induced changes in cAMP activity in adult cardiac myocytes detected with FRET-based biosensor

2005 ◽  
Vol 289 (2) ◽  
pp. C455-C461 ◽  
Author(s):  
Sunita Warrier ◽  
Andriy E. Belevych ◽  
Monica Ruse ◽  
Richard L. Eckert ◽  
Manuela Zaccolo ◽  
...  
Keyword(s):  
Muscarinic Receptor ◽  
Cardiac Myocytes ◽  
Adrenergic Receptor ◽  
Cardiac Myocyte ◽  
Fluorescent Proteins ◽  
Resonance Energy ◽  
Receptor Activation ◽  
Functional Responses ◽  
Adult Cardiac Myocytes ◽  
Camp Activity

β-Adrenergic receptor activation regulates cardiac myocyte function through the stimulation of cAMP production and subsequent activation of protein kinase A (PKA). Furthermore, muscarinic receptor activation inhibits as well as facilitates these cAMP-dependent effects. However, it has not always been possible to correlate the muscarinic responses with the direct measurement of changes in cellular cAMP activity. Genetically encoded biosensors have recently been developed, making it possible to monitor real-time changes in cAMP and PKA activity at the single cell level. One such biosensor consists of the regulatory and catalytic subunits of PKA labeled with cyan and yellow fluorescent proteins, respectively. Changes in cAMP activity affecting the association of these labeled PKA subunits can be detected as changes in fluorescence resonance energy transfer. In the present study, an adenovirus-based approach was developed to express this recombinant protein complex in adult cardiac myocytes and use it to monitor changes in cAMP activity produced by β-adrenergic and muscarinic receptor activation. The biosensor expressed with the use of this system is able to detect changes in cAMP activity produced by physiologically relevant levels of β-adrenergic receptor activation without disrupting normal functional responses. It was also possible to directly demonstrate the complex temporal pattern of inhibitory and stimulatory changes in cAMP activity produced by muscarinic receptor activation in these cells. The adenovirus-based approach we have developed should facilitate the use of this biosensor in studying cAMP and PKA-dependent signaling mechanisms in a wide variety of cell types.

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