Cardiac hypertrophy is a complex process involving the coordinated actions of many genes. In a high throughput screen designed to identify transcripts that are actively translated during cardiac hypertrophy, we identified a number of genes with established links to hypertrophy, including those coding for Sp3, c-Jun, annexin II, cathepsin B, and HB-EGF, thus showing the general utility of the screen. Focusing on a candidate transcript that has not been previously linked to hypertrophy, we found that protein levels of the tumor suppressor PTEN (phosphatase and tensin homologue on chromosome ten) were increased in the absence of increased messenger RNA levels. Increased PTEN expression by recombinant adenovirus in cultured neonatal rat primary cardiomyocytes caused cardiomyocyte apoptosis as evidenced by increased caspase-3 activity and cleaved poly(A)DP-ribose polymerase. Expression of PTEN was also able to block growth factor signaling through the phosphatidylinositol 3,4,5-triphosphate pathway. Surprisingly, expression of a catalytically inactive PTEN mutant led to cardiomyocyte hypertrophy, with increased protein synthesis, cell surface area, and atrial natriuretic factor expression. This hypertrophy was accompanied by an increase in Akt activity and improved cell viability in culture.