Abstract 725: p53-induced Inhibition of Angiogenesis Causes Cardiac Dysfunction during Pressure Overload
Cardiac hypertrophy is formed as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. In this study, we demonstrate that cardiac angiogenesis is critically involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is crucial for the transition from cardiac hypertrophy to heart failure. We produced a chronic pressure overload model by thoracic aortic constriction. In this model, cardiac hypertrophy was initially developed with a peak at day 14 and was significantly decreased by day 28. Cardiac function was preserved by day 14, and significantly reduced at day 28, indicating that pressure overload initially induced adaptive hypertrophy (day 1–14) to preserve cardiac function, however, this adaptive mechanism could not protect the hypertrophied heart against sustained pressure overload, resulting in cardiac dysfunction (day 14 –28). Pressure overload initially promoted vascular growth in the heart through angiogenic factors induced by hypoxia-inducible facror-1 (HIF-1). Inhibition of angiogenesis by the angiogenic inhibitor TNP-470 prevented the development of cardiac hypertrophy and induced cardiac dysfunction. Likewise, pressure overload led to systolic dysfunction when cardiac angiogenesis was inhibited by cardiomyocyte-specific deletion of HIF-1. Sustained pressure overload induced accumulation of p53 that inhibited HIF-1 activity and thereby impaired cardiac angiogenesis and cardiac function. Promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation further developed hypertrophy and restored cardiac dysfunction under chronic pressure overload. Conversely, promoting p53 accumulation reduced cardiac angiogenesis and impaired cardiac function. These results suggest that anti-angiogenic property of p53 has a critical role in the mechanism underlying the transition from cardiac hypertrophy to heart failure.