title: Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity.
abstract: Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakagomi
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Moriya
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Nojima
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Ichimiya
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kamimura
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan. Electronic address: t_minamino@yahoo.co.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063269:Mitochondrial Turnover; D018482:Muscle, Skeletal / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D052250:Nitric Oxide Synthase Type III