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(Circulation Research. 2009;104:e42.)
© 2009 American Heart Association, Inc.

UltraRapid Communication

Age-Accelerated Atherosclerosis Correlates With Failure to Upregulate Antioxidant Genes

Alan R. Collins, Christopher J. Lyon, Xuefeng Xia, Joey Z. Liu, Rajendra K. Tangirala, Fen Yin, Rima Boyadjian, Alfiya Bikineyeva, Domenico Praticò, David G. Harrison, Willa A. Hsueh

From the Methodist Hospital Research Institute (A.R.C., C.J.L., X.X., J.Z.L., W.A.H.), Center for Diabetes Research, Weill Cornell Medical College, Houston, Tex; Division of Endocrinology, Diabetes, and Hypertension (R.K.T., F.Y., R.B.), David Geffen School of Medicine, University of California, Los Angeles; Division of Cardiology (A.B., A.G.H.), Department of Medicine, Emory School of Medicine, Atlanta, Ga; and Department of Pharmacology (D.P.), School of Medicine, Temple University, Philadelphia, Pa.

Correspondence to Willa A. Hsueh, MD, Methodist Hospital Research Institute, Center for Diabetes Research, Weill Cornell Medical College, 6565 Fannin St, F7-070, Houston, TX 77030. E-mail wahsueh{at}tmhs.org

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 F2 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.

Key Words: aging • atherosclerosis • basic research • mouse • oxidative stress

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