Activation of cyclins and cyclin-dependent kinases, DNA synthesis, and myocyte mitotic division in pacing-induced heart failure in dogs.
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/10(6) and 2,467 myocyte nuclei/10(6) in control and paced hearts, respectively. Corresponding mitotic indices were 16/10(6) 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.
Setoguchi
M
M
Department of Medicine, New York Medical College, Valhalla 10595, USA.
Leri
A
A
Wang
S
S
Liu
Y
Y
De Luca
A
A
Giordano
A
A
Hintze
T H
TH
Kajstura
J
J
Anversa
P
P
D000818:Animals; D002304:Cardiac Pacing, Artificial; D002467:Cell Nucleus / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004261:DNA Replication; D004285:Dogs; D004789:Enzyme Activation; D008938:Mitosis; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*
D016213:Cyclins; D018844:Cyclin-Dependent Kinases