p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload - PubMed (original) (raw)

. 2007 Mar 22;446(7134):444-8.

doi: 10.1038/nature05602. Epub 2007 Mar 4.

Tohru Minamino, Haruhiro Toko, Hideyuki Miyauchi, Masayuki Orimo, Yingjie Qin, Hiroshi Akazawa, Kaoru Tateno, Yosuke Kayama, Mutsuo Harada, Ippei Shimizu, Takayuki Asahara, Hirofumi Hamada, Shuhei Tomita, Jeffrey D Molkentin, Yunzeng Zou, Issei Komuro

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p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload

Masanori Sano et al. Nature. 2007.

Abstract

Cardiac hypertrophy occurs 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 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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