title: p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload.
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.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Sano
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyauchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Orimo
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qin
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tateno
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kayama
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harada
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure; D002303:Cardiac Output, Low / Q000503:physiopathology*; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D003326:Coronary Circulation; D018450:Disease Progression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53