Cardiac-specific overexpression of cyclin-dependent kinase 2 increases smaller mononuclear cardiomyocytes

Cyclin-dependent kinase 2 (cdk2) plays a critical role in the G1- to S-phas e checkpoint of the cell cycle. Adult cardiomyocytes are believed to withdr aw from the cell cycle, To determine whether forced overexpression of cdk2 results in altered cell-cycle regulation in the adult heart, we generated t ransgenic mice specifically overexpressing cdk2 in hearts. Transgenic heart s expressed high levels of both cdk2 mRNA and catalytically active cdk2 pro teins. Cdk2 overexpression significantly increased the levels of cdk4 and c yclins A, D3, and E. There was an increase in both DNA synthesis and prolif erating cell nuclear antigen levels in the adult transgenic hearts. The rat io of heart weight to body weight in cdk2 transgenic mice was significantly increased in neonatal day 2 but not in adults compared with that of wild-t ype mice. Analysis of dispersed individual adult cardiomyocytes showed a 5. 6-fold increase in the proportion of smaller mononuclear cardiomyocytes in the transgenic mice. Echocardiography revealed that transgenic heart was fu nctionally normal. However, adult transgenic ventricles expressed beta -myo sin heavy chain and atrial natriuretic factor. Surgically induced pressure overload caused an exaggerated maladaptive hypertrophic response in transge nic mice but did not change the proportion of mononuclear cardiomyocytes. T he data suggest that overexpression of cdk2 promotes smaller, less-differen tiated mononuclear cardiomyocytes in adult hearts that respond in an exagge rated manner to pressure overload.