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Cell Rep. 2014 Jun 12;7(5):1691-1703. doi: 10.1016/j.celrep.2014.04.046. Epub 2014 May 22.

Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity.

Author information

1
Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
2
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
3
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
4
Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
5
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
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.

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.

PMID:
24857662
DOI:
10.1016/j.celrep.2014.04.046
[Indexed for MEDLINE]
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