bcl-2 overexpression promotes myocyte proliferation.
To determine the influence of Bcl-2 on the developmental biology of myocytes, we analyzed the population dynamics of this cell type in the heart of transgenic (TG) mice overexpressing Bcl-2 under the control of the alpha-myosin heavy chain promoter. TG mice and non-TG (wild type, WT) mice were studied at 24 days, 2 months, and 4 months after birth. Bcl-2 overexpression produced a significant increase in the percentage of cycling myocytes and their mitotic index. These effects were strictly connected to the expression of the transgene, as demonstrated in isolated myocytes. The formation of mitotic spindle and contractile ring was identified in replicating cells. These typical aspects of mitosis were complemented with the demonstration of karyokinesis and cytokinesis to provide structural evidence of cell division. Apoptosis was low at all ages and was not affected by Bcl-2. The higher cell replication rate in TG was conditioned by a decrease in the expression of the cell-cycle inhibitors, p21(WAF1) and p16(INK4a), and by an increase in Mdm2-p53 complexes. In comparison with WT, TG had 0.4 x 10(6), 0.74 x 10(6), and 1.2 x 10(6) more myocytes in the left ventricle at 24 days, 2 months, and 4 months, respectively. Binucleated myocytes were 12% and 25% larger in WT than in TG mice at 2 and 4 months of age. Taken together, these observations reveal a previously uncharacterized replication-enhancing function of Bcl-2 in myocytes in vivo in the absence of stressful conditions.
Limana
Federica
F
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Urbanek
Konrad
K
Chimenti
Stefano
S
Quaini
Federico
F
Leri
Annarosa
A
Kajstura
Jan
J
Nadal-Ginard
Bernardo
B
Izumo
Seigo
S
Anversa
Piero
P
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004452:Echocardiography; D006801:Humans; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009132:Muscles / Q000166:cytology*; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size; D010641:Phenotype; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013997:Time Factors; D024723:Ventricular Myosins / Q000235:genetics
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D024723:Ventricular Myosins; D001973:Bromodeoxyuridine