Abstract
Restriction point transit and commitment to a new round of cell division is regulated by the activity of cyclin-dependent kinase 4 and its obligate activating partners, the D-type cyclins. In this study, we examined the ability of D-type cyclins to promote cardiomyocyte cell cycle activity. Adult transgenic mice expressing cyclin D1, D2, or D3 under the regulation of the alpha cardiac myosin heavy chain promoter exhibited high rates of cardiomyocyte DNA synthesis under baseline conditions. Cardiac injury in mice expressing cyclin D1 or D3 resulted in cytoplasmic cyclin D accumulation, with a concomitant reduction in the level of cardiomyocyte DNA synthesis. In contrast, cardiac injury in mice expressing cyclin D2 did not alter subcellular cyclin localization. Consequently, cardiomyocyte cell cycle activity persisted in injured hearts expressing cyclin D2, ultimately resulting in infarct regression. These data suggested that modulation of D-type cyclins could be exploited to promote regenerative growth in injured hearts.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Age Factors
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Animals
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Animals, Newborn
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Cardiomegaly / chemically induced
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Coronary Disease / complications
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Coronary Disease / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / physiology
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Cyclin D2
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Cyclin D3
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases / metabolism
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Cyclins / biosynthesis
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Cyclins / genetics
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Cyclins / physiology*
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DNA Replication*
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Electrocoagulation / adverse effects
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Fibroblasts / metabolism
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Gene Expression Regulation
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Genetic Therapy*
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Heart Injuries / genetics
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Heart Injuries / metabolism
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Heart Injuries / pathology
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Heart Injuries / therapy
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Isoproterenol / toxicity
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Ligation
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Mice
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Mice, Inbred DBA
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Mice, Transgenic
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Myocardial Infarction / genetics
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / therapy*
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Myosin Heavy Chains / genetics
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / metabolism
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Recombinant Fusion Proteins / physiology
Substances
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CCND2 protein, human
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CCND3 protein, human
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Ccnd2 protein, mouse
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Ccnd3 protein, mouse
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Cyclin D2
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Cyclin D3
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Cyclins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Cyclin D1
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Myosin Heavy Chains
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Isoproterenol