Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy

Busk, Peter Kamp; Hinrichsen, Rebecca; Bártková, Jiřina; Hansen, Ane H; Christoffersen, Tue E. H.; Bártek, Jiří; Haunsø, Stig

doi:10.1016/j.yexcr.2004.10.022

Cited by 58 publications

(45 citation statements)

References 56 publications

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“…Overexpression of cyclin D1, a cell cycle activator, and downregulation of p21 impaired hypertrophy induced by Ang II or serum in neonatal and ARVM. 48) These findings suggest that cell cycle progression could be a novel therapeutic strategy for cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 97%

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

Oyama

Takahashi

Sakurai

2011

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 97%

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

Oyama

Takahashi

Sakurai

2011

Biological & Pharmaceutical Bulletin

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“…A number of reports have implicated CycD/ Cdk4 in regulating cardiac hypertrophy in mammalian cells as well, although the downstream effectors have not been identified (25,225). Although forced expression of CycD2 led to cell cycle activation and not hypertrophy in cardiac myocytes (26,175), this might be related to the fact that analogous to the Drosophila model (50), the transgene expression in this study began during fetal development when cardiomyocytes are able to proliferate. Inhibiting G 1 -cyclin/Cdk activity in the adult, postmitotic cardiac myocytes block hypertrophic growth (166,224).…”

Section: A Cyclin/cdk/cdkismentioning

confidence: 87%

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

Ahuja

Sdek²,

MacLellan

2007

Physiological Reviews

507

475

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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.

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“…Additionally, it has been demonstrated that cyclin D2 represses hypertrophy by forcing cardiomyocytes through the cell cycle, resulting in cell proliferation. This suggests that cyclin D2 levels directly determine whether cells grow by hypertrophy or proliferation (Busk et al, 2005). Hand1 has been shown to be downregulated in human ischemic and dilated cardiomyopathies (Natarajan et al, 2001), and also following the induction of cardiac hypertrophy in adult rodent hearts (Thattaliyath et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…As cardiomyocytes develop, they lose the ability to proliferate and there appears to be a block in the gap phases of the cell cycle, most notably at G1, consistent with the terminal differentiation of these cells (Brooks et al, 1998). Progression through G1 is dependent upon the D-type cyclins and, although many different stimuli induce cell proliferation through different signalling pathways, activation of one or more of the D-type cyclins is necessary for most, if not all, of these pathways (Busk et al, 2005). In Hand1-overexpressing EBs, we observed significantly elevated protein levels of both cyclin D2 and Cdk4 compared with wild type; this was reciprocated by reduced levels for both proteins in EBs that were either heterozygous RESEARCH ARTICLE Development 133 (22) or homozygous mutant for Hand1 (Fig.…”

Section: Research Articlementioning

confidence: 96%

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart

Risebro¹,

Smart²,

Dupays³

et al. 2006

Development

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The precise origins of myocardial progenitors and their subsequent contribution to the developing heart has been an area of considerable activity within the field of cardiovascular biology. How these progenitors are regulated and what signals are responsible for their development are, however,much less well understood. Clearly, not only is there a need to identify factors that regulate the transition from proliferation of cardioblasts to differentiation of cardiac muscle, but it is also necessary to identify factors that maintain an adequate pool of undifferentiated myocyte precursors as a prerequisite to preventing organ hypoplasia and congenital heart disease. Here, we report how upregulation of the basic helix-loop-helix (bHLH)transcription factor Hand1, restricted exclusively to Hand1-expressing cells, brings about a significant extension of the heart tube and extraneous looping caused by the elevated proliferation of cardioblasts in the distal outflow tract. This activity is independent of the further recruitment of extracardiac cells from the secondary heart field and permissive for the continued differentiation of adjacent myocardium. Culture studies using embryonic stem (ES) cell-derived cardiomyocytes revealed that,in a Hand1-null background, there is significantly elevated cardiomyocyte differentiation, with an apparent default mesoderm pathway to a cardiomyocyte fate. However, Hand1 gain of function maintains proliferating precursors resulting in delayed and significantly reduced cardiomyocyte differentiation that is mediated by the prevention of cell-cycle exit, by G1 progression and by increased cell division. Thus, this work identifies Hand1 as a crucial cardiac regulatory protein that controls the balance between proliferation and differentiation in the developing heart, and fills a significant gap in our understanding of how the myocardium of the embryonic heart is established.

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Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy

Cited by 58 publications

References 56 publications

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

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

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart

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