Age-Accelerated Atherosclerosis Correlates With Failure to Upregulate Antioxidant Genes. Export

@article{citeulike:4153038, 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.}, author = {Collins, Alan R R. and Lyon, Christopher J J. and Xia, Xuefeng and Liu, Joey Z Z. and Tangirala, Rajendra K K. and Yin, Fen and Boyadjian, Rima and Bikineyeva, Alfiya and Pratic\`{o}, Domenico and Harrison, David G G. and Hsueh, Willa A A.}, citeulike-article-id = {4153038}, citeulike-linkout-0 = {http://dx.doi.org/10.1161/CIRCRESAHA.108.188771}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19265038}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19265038}, day = {5}, doi = {10.1161/CIRCRESAHA.108.188771}, issn = {1524-4571}, journal = {Circulation research}, keywords = {aging, antioxidant\_genes, atherosclerosis}, month = {March}, posted-at = {2009-03-08 22:13:10}, priority = {3}, title = {Age-Accelerated Atherosclerosis Correlates With Failure to Upregulate Antioxidant Genes.}, url = {http://dx.doi.org/10.1161/CIRCRESAHA.108.188771}, year = {2009} }

TY - JOUR ID - citeulike:4153038 L3 - citeulike-article-id:4153038 N2 - 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. JF - Circulation research SN - 1524-4571 TI - Age-Accelerated Atherosclerosis Correlates With Failure to Upregulate Antioxidant Genes. KW - aging KW - antioxidant_genes KW - atherosclerosis AU - Collins, Alan R AU - Lyon, Christopher J AU - Xia, Xuefeng AU - Liu, Joey Z AU - Tangirala, Rajendra K AU - Yin, Fen AU - Boyadjian, Rima AU - Bikineyeva, Alfiya AU - Praticò, Domenico AU - Harrison, David G AU - Hsueh, Willa A PY - 2009/03/05/ UR - http://dx.doi.org/10.1161/CIRCRESAHA.108.188771 ER -