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Letter
Nature 446, 444-448 (22 March 2007) | doi:10.1038/nature05602; Received 1 November 2006; Accepted 15 January 2007; Published online 4 March 2007
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p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload
Masanori Sano1,7, Tohru Minamino1,7, Haruhiro Toko1, Hideyuki Miyauchi1, Masayuki Orimo1, Yingjie Qin1, Hiroshi Akazawa1, Kaoru Tateno1, Yosuke Kayama1, Mutsuo Harada1, Ippei Shimizu1, Takayuki Asahara2, Hirofumi Hamada3, Shuhei Tomita4, Jeffrey D. Molkentin5, Yunzeng Zou6 & Issei Komuro1
- Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
- Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
- Department of Molecular Medicine, Sapporo Medical University, S1 W17, Chuo-ku, Sapporo 060-8556, Japan
- Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan
- Department of Pediatrics, Children's Hospital Medical Center, Division of Molecular Cardiovascular Biology, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
- These authors contributed equally to this work.
Correspondence to: Issei Komuro1 Correspondence and requests for materials should be addressed to I.K. (Email: komuro-tky@umin.ac.jp).
Abstract
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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