Like most other cells in the body, foetal and neonatal cardiac myocytes are able to divide and proliferate. However, the ability of these cells to undergo cell division decreases progressively during development such that adult myocytes are unable to divide. A major problem arising from this inability of adult cardiac myocytes to proliferate is that the mature heart is unable to regenerate new myocardial tissue following severe injury, e.g. infarction, which can lead to compromised cardiac pump function and even death. Studies in proliferating cells have identified a group of genes and proteins that controls cell division. These proteins include cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs), which interact with each other to form complexes that are essential for controlling normal cell cycle progression. A variety of other proteins, e.g. the retinoblastoma protein (pRb) and members of the E2F family of transcription factors, also can interact with, and modulate the activities of, these complexes. Despite the major role that these proteins play in other cell types, little was known until recently about their existence and activities in immature (proliferating) or mature (non-proliferating) cardiac myocytes. The reason(s) why cardiac myocytes lose their ability to divide during development remains unknown, but if strategies were developed to understand the mechanisms underlying cardiac myocyte growth, it could open up new avenues for the treatment of cardiovascular disease. In this article, we shall review the function of the cell cycle machinery and outline some of our recent findings pertaining to the involvement of the cell cycle in modulating cardiac myocyte growth and hypertrophy.

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Abstract-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 KIP1 in the mouse results in a significant increase in heart size and in the total number of cardiac myocytes. In comparison to p27 KIP1 ϩ/ϩ myocytes, the percentage of neonatal p27 KIP1 Ϫ/Ϫ myocytes in S phase was increased significantly, concomitant with a significant decrease in the percentage of G 0 /G 1 cells. The expressions of proliferating cell nuclear antigen, G 1 /S and G 2 /M phase-acting cyclins, and cyclin-dependent kinases (CDKs) were upregulated significantly in ventricular tissue obtained from early neonatal p27 KIP1 Ϫ/Ϫ mice, concomitant with a substantial decrease in the expressions of G 1 phase-acting cyclins and CDKs. Furthermore, mRNA expressions of the embryonic genes atrial natriuretic factor and ␣-skeletal actin were detectable at significant levels in neonatal and adult p27 KIP1 Ϫ/Ϫ mouse hearts but were undetectable in p27 KIP1 ϩ/ϩ hearts. In addition, loss of p27 KIP1 was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27