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Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus

¹Department of Physiology, New York Medical College, Valhalla, New York; ²Laboratory of Physiological Studies, Section on Oxidative Stress Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; ³Department of Biological Sciences and the Peromyscus Stock Center, University of South Carolina, Columbia, South Carolina; ⁴Department of Pulmonology, Semmelweis University, Budapest, Hungary; Departments of ⁵Biochemistry, ⁶Cell Biology and Anatomy, and ⁷Pediatrics, New York Medical College, Valhalla, New York; and ⁸The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, Texas

Submitted 7 July 2008 ; accepted in final form 23 January 2009

Vascular aging is characterized by increased oxidative stress and proinflammatory phenotypic alterations. Metabolic stress, such as hyperglycemia in diabetes, is known to increase the production of ROS and promote inflammatory gene expression, accelerating vascular aging. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower steady-state production of ROS and/or superior resistance to the prooxidant effects of metabolic stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), which show a more than twofold difference in maximum lifespan potential (8.2 and 3.5 yr, respectively). We compared interspecies differences in steady-state and high glucose (HG; 30 mmol/l)-induced production of O₂^– and H₂O₂, endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady-state endothelial O₂^– and H₂O₂ production and ROS generation by mitochondria were less than in M. musculus vessels. Furthermore, vessels of P. leucopus were more resistant to the prooxidant effects of HG. Primary fibroblasts from P. leucopus also exhibited less steady-state and HG-induced ROS production than M. musculus cells. In M. musculus arteries, HG elicited significant upregulation of inflammatory markers (TNF-, IL-6, ICAM-1, VCAM, and monocyte chemoattractant protein-1). In contrast, the proinflammatory effects of HG were blunted in P. leucopus vessels. Thus, increased life span potential in P. leucopus is associated with decreased cellular ROS generation and increased resistance to prooxidant and proinflammatory effects of metabolic stress, which accord with predictions of the oxidative stress hypothesis of aging.

senescence; comparative biology; vascular disease; atherosclerosis

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