| Authors |
Collins AR, Lyon CJ, Xia X, Liu JZ, Tangirala RK, Yin F, Boyadjian R, Bikineyeva
A, Pratic貌 D, Harrison DG, Hsueh WA
|
| Submitted By |
Willa Hsueh on 3/4/2015 |
| Status |
Published |
| Journal |
Circulation research |
| Year |
2009 |
| Date Published |
3/27/2009 |
| Volume : Pages |
104 : e42 - e54 |
| PubMed Reference |
|
| Abstract |
Excess food intake leads to obesity and diabetes, both of which are well-known
independent risk factors for atherosclerosis, and both of which are growing
epidemics in an aging population. We hypothesized that aging enhances the
metabolic and vascular effects of high fat diet (HFD) and therefore examined the
effect of age on atherosclerosis and insulin resistance in lipoprotein receptor
knockout (LDLR(-/-)) mice. We found that 12-month-old (middle-aged) LDLR(-/-)
mice developed substantially worse metabolic syndrome, diabetes, and
atherosclerosis than 3-month-old (young) LDLR(-/-) mice when both were fed HFD
for 3 months, despite similar elevations in total cholesterol levels. Microarray
analyses were performed to analyze the mechanism responsible for the marked
acceleration of atherosclerosis in middle-aged mice. Chow-fed middle-aged mice
had greater aortic expression of multiple antioxidant genes than chow-fed young
mice, including glutathione peroxidase-1 and -4, catalase, superoxide
dismutase-2, and uncoupling protein-2. Aortic expression of these enzymes
markedly increased in young mice fed HFD but decreased or only modestly
increased in middle-aged mice fed HFD, despite the fact that systemic oxidative
stress and vascular reactive oxygen species generation, measured by plasma
F2alpha isoprostane concentration (systemic) and dihydroethidium conversion and
p47phox expression (vascular), were greater in middle-aged mice fed HFD. Thus,
the mechanism for the accelerated vascular injury in older LDLR(-/-) mice was
likely the profound inability to mount an antioxidant response. This effect was
related to a decrease in vascular expression of 2 key transcriptional pathways
regulating the antioxidant response, DJ-1 and forkhead box, subgroup O family
(FOXOs). Treatment of middle-aged mice fed HFD with the antioxidant apocynin
attenuated atherosclerosis, whereas treatment with the insulin sensitizer
rosiglitazone attenuated both metabolic syndrome and atherosclerosis. Both
treatments decreased oxidative stress. A novel effect of rosiglitazone was to
increase expression of Nrf2 (nuclear factor [erythroid-derived 2]-like 2), a
downstream target of DJ-1 contributing to enhanced expression of vascular
antioxidant enzymes. This investigation underscores the role of oxidative stress
when multiple atherosclerotic risk factors, particularly aging, converge on the
vessel wall and emphasizes the need to develop effective strategies to inhibit
oxidative stress to protect aging vasculature.
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