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Activation
of Cyclins and Cyclin-Dependent Kinases, DNA Synthesis, and Myocyte Mitotic
Division in Pacing-Induced Heart Failure in Dogs |
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Manabu Setoguchi,
Annarosa Leri, Shenglun Wang, Yu Liu, Antonio De Luca, Antonio Giordano,
Thomas H. Hintze, Jan Kajstura, and Piero Anversa |
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Departments
of Medicine (MS, AL, SW, YL, JK, PA) and Physiology (THH), New York Medical
College, Valhalla, New York; and Department of Pathology, Anatomy and Cell
Biology and Institute for Cancer Research and Molecular Medicine (ADL, AG),
Jefferson Medical College, Philadelphia, Pennsylvania |
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SUMMARY: The inability of
myocytes to reenter the cell cycle in vitro may result from a block in the
activation of cyclins and cyclin-dependent kinases (cdk). This inhibition
may not occur in vivo because myocyte proliferation is present in the failing
heart. Thus, cardiac failure was induced by ventricular pacing in dogs,
and changes in the quantity of cyclin D2, cyclin A, cyclin B,
cdk2, and cell-division cycle-2 (cdc2) in control
and paced myocytes were measured. The kinase activity of these nuclear proteins
was also established. Finally, DNA synthesis and mitotic indices in myocytes
were evaluated. Cyclin D2 in myocytes increased 7-fold after
pacing, and cyclin D2-associated kinase activity increased 3-fold.
Similarly, cyclin A quantity and activity increased 4-fold. Comparable changes
were observed for cyclin B. cdc2 protein increased 8-fold, and
cdk2 and cdc2 activity increased 3-fold and 5-fold,
respectively. DNA synthesis was detected in 556 myocyte nuclei/106
and 2,467 myocyte nuclei/106 in control and paced hearts, respectively.
Corresponding mitotic indices were 16/106 and 95/106,
respectively. In conclusion, myocytes react to cardiac failure by activating
cyclins and cdk, which are coupled with cell regeneration and the recovery
of muscle mass. |
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