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 fro m a block in the activation of cyclins and cyclin-dependent kinases (cdk). This inhibition may not occur in vivo because myocyte proliferation is pres ent in the failing heart. Thus, cardiac failure was induced by ventricular pacing in dogs, and changes in the quantity of cyclin D-2, cyclin A, cyclin B, cdk(2), and cell-division cycle-2 (cdc(2)) in control and paced myocyte s were measured. The kinase activity of these nuclear proteins was also est ablished. Finally, DNA synthesis and mitotic indices in myocytes were evalu ated. Cyclin D-2 in myocytes increased 7-fold after pacing, and cyclin D-2- associated kinase activity increased 3-fold. Similarly, cyclin A quantity a nd activity increased 4-fold. Comparable changes were observed for cyclin B . cdc(2) protein increased 8-fold, and cdk(2) and cdc(2) 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, r espectively. Corresponding mitotic indices were 16/10(6) and 95/10(6), resp ectively. In conclusion, myocytes react to cardiac failure by activating cy clins and cdk, which are coupled with cell regeneration and the recovery of muscle mass.