The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival

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 n umber of genes with established links to hypertrophy, including those codin g for Sp3, e-Jun, annexin II, cathepsin B, and HB-EGF, thus showing the gen eral 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 ca spase-3 activity and cleaved poly(A)DP-ribose polymerase. Expression of PTE N was also able to block growth factor signaling through the phosphatidylin ositol 3,4,5-triphosphate pathway. Surprisingly, expression of a catalytica lly inactive PTEN mutant led to cardiomyocyte hypertrophy, with increased p rotein synthesis, cell surface area, and atrial natriuretic factor expressi on. This hypertrophy was accompanied by an increase in Akt activity and imp roved cell viability in culture.