Altered Expression of Cell Cycle Proteins and Prolonged Duration of Cardiac Myocyte Hyperplasia in p27 Knockout Mice

The precise role of cell cycle–dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains to be determined. We report that loss of p27 in the mouse results in a significant increase in heart size and in the total number of cardiac myocytes. In comparison to p271/1 myocytes, the percentage of neonatal p272/2 myocytes in S phase was increased significantly, concomitant with a significant decrease in the percentage of G0/G1 cells. The expressions of proliferating cell nuclear antigen, G1/S and G2/M phase–acting cyclins, and cyclin-dependent kinases (CDKs) were upregulated significantly in ventricular tissue obtained from early neonatal p272/2 mice, concomitant with a substantial decrease in the expressions of G1 phase–acting cyclins and CDKs. Furthermore, mRNA expressions of the embryonic genes atrial natriuretic factor and a-skeletal actin were detectable at significant levels in neonatal and adult p272/2 mouse hearts but were undetectable in p271/1 hearts. In addition, loss of p27 was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27 results in prolonged proliferation of the mouse cardiac myocyte and perturbation of myocyte hypertrophy. (Circ Res. 1999;85:117-127.)