Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function1. However, prolonged cardiac hypertrophy causes heart failure2, 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 initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and 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 indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.
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We thank E. Fujita, R. Kobayashi and M. Ikeda for technical support. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas and for Exploratory Research, Ministry of Education, Culture, Sports, Science and Technology; Health and Labour Sciences Research Grants; Research on Measures for Intractable Diseases; Grants from Goho Life Sciences International Fund; an Academic Award of the Mochida Memorial Foundation and Uehara Memorial Foundation (to I.K.); and grants from the Suzuken Memorial Foundation, the NOVARTIS Foundation and the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T.M.).
Author Contributions M.S., T.M., H.T., H.M., M.O., Y.Q., H.A., K.T., Y.K., M.H., I.S. and Y.Z. performed the experiments. T.A., H.H., S.T. and J.D.M. provided reagents or mice. M.S., T.M. and I.K. designed and prepared the manuscript. I.K. planned and supervised the project.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains Supplementary Figures 1–11 with Legends, Supplementary Methods describing all reagents used as well as detailed protocols and additional references. (PDF 1083 kb)
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Sano, M., Minamino, T., Toko, H. et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446, 444–448 (2007). https://doi.org/10.1038/nature05602
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