Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

Engel, Felix B.

doi:10.4161/cc.4.10.2081

Cited by 56 publications

(49 citation statements)

References 37 publications

(52 reference statements)

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“…Stimuli-Some of the cell cycle regulators are known to be increased with several mitogenic stimuli in primary cardiomyocytes (23,24,29,36,37). As shown in Fig.…”

Section: P21 Is Stabilized In Cardiomyocytes In Response To Mitogenicmentioning

confidence: 99%

Degradation of p21Cip1 through Anaphase-promoting Complex/Cyclosome and Its Activator Cdc20 (APC/CCdc20) Ubiquitin Ligase Complex-mediated Ubiquitylation Is Inhibited by Cyclin-dependent Kinase 2 in Cardiomyocytes

Yamada

Tamamori‐Adachi

Goto

et al. 2011

Journal of Biological Chemistry

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Background: p21Cip1 is controlled by both a transcriptional and post-translational mechanism during cell cycle progression and differentiation. Results: CDK2 blocks APC/C Cdc20 -mediated ubiquitylation of p21 at the N terminus, causing G 2 arrest in mitogen-stimulated cardiomyocytes. Conclusion:The regulation of p21 ubiquitylation is required to maintain a terminal differentiation state of cardiomyocytes.Significance: This provides a novel insight on the control of cell cycle arrest in terminal differentiation.

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“…Stimuli-Some of the cell cycle regulators are known to be increased with several mitogenic stimuli in primary cardiomyocytes (23,24,29,36,37). As shown in Fig.…”

Section: P21 Is Stabilized In Cardiomyocytes In Response To Mitogenicmentioning

confidence: 99%

Degradation of p21Cip1 through Anaphase-promoting Complex/Cyclosome and Its Activator Cdc20 (APC/CCdc20) Ubiquitin Ligase Complex-mediated Ubiquitylation Is Inhibited by Cyclin-dependent Kinase 2 in Cardiomyocytes

Yamada

Tamamori‐Adachi

Goto

et al. 2011

Journal of Biological Chemistry

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“…Identifying the key regulators of cardiomyocyte proliferation and understanding the Cardiovascular Research 74 (2007) 304 -312 www.elsevier.com/locate/cardiores molecular mechanisms involved in limiting the ability of cardiomyocytes to divide, therefore, is crucial if we are to develop new therapies to treat such heart diseases. The loss in the ability of differentiated adult cardiomyocytes to divide has been the focus of interest for a number of researchers [6,7]. During cardiac development, it has been observed that changes in the proliferative capacity of cardiomyocytes coincide with a biochemical block in cardiac cell cycle progression leading to terminal differentiation [2,8].…”

Section: Introductionmentioning

confidence: 99%

Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation

McKoy

Bicknell

Patel

et al. 2007

Cardiovascular Research

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Objectives: Myostatin, a member of the transforming growth factor-beta (TGF-β) family, plays a key role in skeletal muscle myogenesis by limiting hyperplastic and hypertrophic muscle growth. In cardiac muscle, myostatin has been shown to limit agonist-induced cardiac hypertrophic growth. However, its role in cardiac hyperplastic growth remains undetermined. The aim of this study was to characterise the expression of myostatin in developing myocardium, determine its effect on cardiomyocyte proliferation, and explore the signalling mechanisms affected by myostatin in dividing cardiomyocytes. Methods: We used quantitative PCR and Western blotting to study the expression of myostatin in cardiomyocytes isolated from rat myocardium at different developmental ages. We determined the effect of recombinant myostatin on proliferation and cell viability in dividing cardiomyocytes in culture. We analysed myostatin's effect on cardiomyocyte cell cycle progression by flow cytometry and used Western blotting to explore the signalling mechanisms involved. Results: Myostatin is expressed differentially in cardiomyocytes during cardiac development such that increasing expression correlated with a low cardiomyocyte proliferation index. Proliferating foetal cardiomyocytes, from embryos at 18 days of gestation, expressed low levels of myostatin mRNA and protein, whereas isolated cardiomyocytes from postnatal day 10 hearts, wherein the majority of cardiomyocytes have lost their ability to proliferate, displayed a 6-fold increase in myostatin expression. Our in vitro studies demonstrated that myostatin inhibited proliferation of dividing foetal and neonatal cardiomyocytes. Flow cytometric analysis showed that this inhibition occurs mainly via a block in the G1-S phase transition of the cardiomyocyte cell cycle. Western blot analysis showed that part of the mechanism underpinning the inhibition of cardiomyocyte proliferation by myostatin involves phosphorylation of SMAD2 and altered expressions of the cell cycle proteins p21 and CDK2. Conclusions: We conclude that myostatin is an inhibitor of cardiomyocyte proliferation with the potential to limit cardiomyocyte hyperplastic growth by altering cardiac cell cycle progression.

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“…The permanent loss of cardiomyocytes following myocardial infarction (MI) often results in heart failure. Potential therapies could include stimulating the myocytes to divide and adding new cells via pharmacological and genetic manipulations or delivering stem cells to multiply and subsequently differentiate into cardiomyocytes (7). Recent reports have shown that adult cardiac myocytes can be induced to reenter into cell cycle with periostin (17), p38 MAP kinase inhibitor (8), cyclin D1/CDK4 (27), cyclin A2 (3), and transforming growth factor-␤ (4).…”

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confidence: 99%

Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction

Wang¹,

Zhang²,

Ashraf³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 298: H275-H286, 2010. First published November 6, 2009 doi:10.1152/ajpheart.00765.2009.-Neuropeptide Y (NPY) induced reentry of differentiated rat neonatal and adult cardiomyocytes into the cell cycle. NPY also induced differentiation of bone marrow-derived mesenchymal stem cells (MSC) into cardiomyocytes following transplantation into infarcted myocardium. Rat neonatal and adult cardiomyocytes were treated in vitro with vehicle, NPY, fibroblast growth factor (FGF; 100 ng/ml), or FGF plus NPY. DNA synthesis, mitosis, and cytokinesis were determined by immunocytochemistry. NPY-induced MSC gene expression, cell migration, tube formation, and endothelial cell differentiation were analyzed. Male rat green fluorescent protein-MSC (2 ϫ 10 6 ), pretreated with either vehicle or NPY (10 Ϫ8 M) for 72 h, were injected into the border zone of the female myocardium following left anterior descending artery ligation. On day 30, heart function was assessed, and hearts were harvested for histological and immunohistochemical analyses. NPY increased 5-bromo-2Ј-deoxy-uridine incorporation and promoted both cytokinesis and mitosis in rat neonatal and adult myocytes. NPY also upregulated several genes required for mitosis in MSC, including aurora B kinase, FGF-2, cycline A2, eukaryotic initiation factor 4 E, and stromal cell-derived factor-1␣. NPY directly induced neonatal and adult cardiomyocyte cell-cycle reentry and enhanced the number of differentiated cardiomyocytes from MSC in the infarcted myocardium, which corresponded to improved cardiac function, reduced fibrosis, ventricular remodeling, and increased angiomyogenesis. It is concluded that a combined treatment of NPY with MSC is a novel approach for cardiac repair. deoxyribonucleic acid synthesis FETAL AND NEONATAL CARDIAC myocytes are capable of undergoing DNA synthesis and cell division. However, their ability to divide diminishes progressively during postnatal development (2). Adult mammalian cardiomyocytes are considered terminally differentiated, incapable of proliferation and irreversibly withdrawn from the cell cycle soon after birth (28, 29). The permanent loss of cardiomyocytes following myocardial infarction (MI) often results in heart failure. Potential therapies could include stimulating the myocytes to divide and adding new cells via pharmacological and genetic manipulations or delivering stem cells to multiply and subsequently differentiate into cardiomyocytes (7). Recent reports have shown that adult cardiac myocytes can be induced to reenter into cell cycle with periostin (17), p38 MAP kinase inhibitor (8), cyclin D1/CDK4 (27), cyclin A2 (3), and transforming growth factor-␤ (4).Although the adult heart has a limited capacity for myocyte proliferation, increasing the number of remaining cardiomyocytes by activating their proliferative potential via extrinsic factors could result in the repair of damaged myocardium. Therefor...

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Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

Cited by 56 publications

References 37 publications

Degradation of p21Cip1 through Anaphase-promoting Complex/Cyclosome and Its Activator Cdc20 (APC/CCdc20) Ubiquitin Ligase Complex-mediated Ubiquitylation Is Inhibited by Cyclin-dependent Kinase 2 in Cardiomyocytes

Degradation of p21Cip1 through Anaphase-promoting Complex/Cyclosome and Its Activator Cdc20 (APC/CCdc20) Ubiquitin Ligase Complex-mediated Ubiquitylation Is Inhibited by Cyclin-dependent Kinase 2 in Cardiomyocytes

Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation

Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction

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