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(Circulation Research. 1999;85:117-127.)
© 1999 American Heart Association, Inc.

Original Contribution

Altered Expression of Cell Cycle Proteins and Prolonged Duration of Cardiac Myocyte Hyperplasia in p27^KIP1 Knockout Mice

Robert A. Poolman, Jian-Mei Li, Beatrice Durand, Gavin Brooks

From Cardiovascular Cellular and Molecular Biology (R.A.P., J.-M.L., G.B.), The Rayne Institute, St. Thomas' Hospital, London, UK; MRC Laboratory of Molecular and Cellular Biology (B.D.), MRC Developmental Neurobiology Programme, University College London, London, UK; and School of Animal and Microbial Sciences (G.B.), University of Reading, Whiteknights, Reading, UK.

Correspondence and reprint requests to Dr Gavin Brooks, School of Animal and Microbial Sciences, University of Reading, Whiteknights, PO Box 228, Reading, RG6 6AJ, Berks, England. E-mail G.Brooks{at}reading.ac.uk

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+/+ myocytes, the percentage of neonatal p27^KIP1-/- 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 p27^KIP1-/- 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 -skeletal actin were detectable at significant levels in neonatal and adult p27^KIP1-/- mouse hearts but were undetectable in p27^KIP1+/+ hearts. In addition, loss of p27^KIP1 was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27^KIP1 results in prolonged proliferation of the mouse cardiac myocyte and perturbation of myocyte hypertrophy.

Key Words: cardiac myocyte • cell cycle • p27^KIP1 • hyperplasia • mouse

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