Abstract 11062: Constitutive Low Levels of P53 Expression Maintain Vascular Endothelial Function in Mice Fed a High Fat Diet
Stress associated with aging, oxidative stress and high glucose lead to a vascular over-expression of the tumour suppressor gene p53. Paradoxically, however, lack of p53 in mice accelerates atherosclerotic plaque formation. We therefore hypothesized that p53 is essential to maintain vascular homeostasis by detecting stress, stimulating the expression of defence mechanisms initially preserving the endothelial function. To test our hypothesis, we used 3-month old (mo) C57Bl/6J (WT) and p53+/- male mice that express constitutive low levels of p53. Mice were then fed a regular (RD) or high fat diet (HFD) for 3 months. In WT mice, the maximal endothelium-dependent relaxation of the aorta induced by acetylcholine declined from 100±0% to 62±5% (p=0.01, n=9) at 6-mo. This decline, however, was not observed in mice fed a HFD (87±2%, p=0.02): it was associated with a 2-fold increase in the activity of the superoxide dismutase 2 (SOD2) in the aorta (p=0.01; n=3) without changes in aortic oxidative stress level measured by immunofluorescence. HFD-induced stress was further evidenced by a 2-fold rise in plasma levels of the pro-atherosclerotic keratinocyte-derived chemokine (p=0.02; n=5). In addition, while LDL-cholesterol doubled (p=0.01; n=7), gene expression of the hepatic Cyp7A1, the main enzyme responsible for bile acid synthesis, was induced by the HFD in WT mice from 1.0±0.2 to 2.1±0.4 a.u. (p=0.02, n=5). In contrast to WT mice, the endothelial function did not decline with age in p53+/- mice (93±3 and 82±4%, respectively) expressing low constitutive levels of p53, and was not affected by the HFD (83±5%; n=5). Neither SOD2 activity, the expression of the keratinocyte-derived chemokine, nor LDL-cholesterol were increased by the HFD in p53+/- mice, while the hepatic expression of the Cyp7A1 gene was constitutively greater (RD=2.3±0.3, HFD=2.4±0.7 a.u.). We conclude that low constitutive level of expression of p53 in the p53+/- mouse is associated with a favourable cardiovascular profile protective against HFD. We propose that HFD induces a stress that triggers a p53-dependent expression of vascular defence mechanisms as evidenced in the WT mice.
- © 2012 by American Heart Association, Inc.