The major findings in the present study are that (1) PDCD5 expression is significantly up-regulated in cardiac hypertrophy; (2) Cardiac specific high over-expression of hPDCD5 results in dilated cardiomyopathy, heart failure and premature sudden death; (3) Autophagy is dramatically up-regulated in transgenic mice with high hPDCD5 over-expression, which is associated with increased p53 activity; (4) Low PDCD5 over-expressing line is more susceptible to Ang II-induced cardiac hypertrophy. Here, PDCD5 is linked to dilated cardiomyopathy.