Cardiac hypertrophy is developed as an adaptive response to increased workload to maintain cardiac function. However， prolonged cardiac hypertrophy causes heart failure， and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure.
Pressure overload， which is produced by constricting transverse aorta of mice， induced cardiac hypertrophy without cardiac dysfunction until 14 days and initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors. After 14 days， however， there was no further cardiac hypertrophy but cardiac function was decreased， and the vascular density was reduced with downregulation of Hif-1 and angiogenic growth factors. Inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely， promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results suggest that the anti-angiogenic property of p53 has a crucial function in the transition from cardiac hypertrophy to heart failure and that angiogenic therapy is effective to treat heart failure.