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

Abstract

Labinskyy N, Mukhopadhyay P, Toth J, Szalai G, Veres M, Losonczy G, Pinto JT, Pacher P, Ballabh P, Podlutsky A, Austad SN, Csiszar A, Ungvari Z. Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296: H946 -H956, 2009. First published January 30, 2009 doi:10.1152/ajpheart.00693.2008.-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 O 2•Ϫ and H2O2, endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady-state endothelial O 2•Ϫ 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 AGE IS A MAJOR RISK FACTOR for cardiovascular disease, which remains the leading cause of morbidity and mortality of older Americans. Despite recent advances in the biology of aging, the factors determining successful cardiovascular aging are still not completely understood (15, 53, 54). Mammalian life span ranges 100-fold, and comparative studies (53, 54) on longlived, successfully aging animals can elucidate key cellular mechanisms that may contribute importantly to successful cardiovascular aging. We initiated a series of studies to compare mechanisms related to oxidative stress, oxidative stress resistance, and redox signaling between long-living species and shorter-living ones to test predictions of the oxidative stress t...

Reduced mitochondrial ROS, enhanced antioxidant defense, and distinct age-related changes in oxidative damage in muscles of long-lived Peromyscus leucopus

“…Our data showing reduced production of H 2 O 2 and O 2 ·Ϫ in skeletal muscle mitochondria are consistent with previous studies from other tissues in P. leucopus (12,21,39,66). In the brain, heart, and endothelial cells of P. leucopus, investigators demonstrate a low rate of mitochondrial O 2 ·Ϫ and H 2 O 2 generation (39,58), high activities of catalase and glutathione peroxidase (21,58), low levels of oxidative damage to proteins (32,58), delayed accumulation of DNA damage (62), and enhanced resistance to oxidative stress in vitro (21,66) compared with M. musculus.…”

“…In the brain, heart, and endothelial cells of P. leucopus, investigators demonstrate a low rate of mitochondrial O 2 ·Ϫ and H 2 O 2 generation (39,58), high activities of catalase and glutathione peroxidase (21,58), low levels of oxidative damage to proteins (32,58), delayed accumulation of DNA damage (62), and enhanced resistance to oxidative stress in vitro (21,66) compared with M. musculus. Interestingly, we found that the levels of H 2 O 2 and O 2 ·Ϫ are lower, even when inhibitors (rotenone or antimycin A) were added to stimulate their maximal production.…”

Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response

“…3) (8, 18, 56). The intimate link among aging, Nrf2 activation, and vascular health is also underscored by the observations that arteries of extremely longlived muroid rodents (P. leucopus, maximal lifespan: ϳ8 years) exhibit an increased expression of Nrf2-driven antioxidant enzymes, decreased cellular and mitochondrial levels of ROS, and increased resistance to the proinflammatory and proapoptotic effects of hyperglycemia compared with vessels of shorter-lived M. musculus (13,33,50,54).…”

“…Aorta segments isolated from young and aged rats were maintained in organoid culture (for 24 h) as previously described (60). Vessels were treated with H 2O2 (from 10 Ϫ6 to 10 Ϫ4 mol/l) or high glucose (30 mmol/l), which effectively increases mitochondrial H2O2 generation (33). At the end of the culture period nuclear Nrf2 binding activity, expression of Nrf2 targets, production of ROS, and apoptotic cell death were assayed as described below.…”

Beneficial Effect of Viscous Fermented Milk on Blood Glucose and Insulin Responses to Carbohydrates in Mice and Healthy Volunteers: Preventive Geriatrics Approach by "Slow Calorie"

“…The lower AI/AG as well as the slower increase of plasma glucose level after F/R meal than that after M/R meal implied that the Caspian Sea Yogurt would increase insulin efficiency. Remarkable characteristics of the Caspian Sea Yogurt consumption before complex carbohydrate intake such as lower AI/AG and peak delay in postprandial glucose level would play an important role for prevention of vascular aging caused by high glucose induced oxidative stress (Labinskyy et al, 2009). Furthermore, slow rise of postprandial glucose level may be beneficial on vascular endothelial cells, since intermittent high glucose rather than constant high glucose was revealed to enhance reactive oxygen species-induced apoptosis in human umbilical vein endothelial cells (Risso et al, 2001, Quagliaro et al, 2003.…”