Spontaneous Experimental Atherosclerosis In Hypercholesterolemic Mice Advances With Ageing And Correlates With Mitochondrial Reactive Oxygen Species

Ageing and atherosclerosis are associated with oxidative stress. Mitochondrial redox function declines with ageing. Here we tested whether ageing LDL receptor knockout mice (LDLr-/-) develop spontaneous atherosclerosis and whether mitochondrial reactive oxygen species (mtROS) correlate with atherosclerosis. Compared with young mice, aged LDLr-/- mice exhibited 20-fold larger aortic lesion size, although the plasma cholesterol levels did not vary between age groups. The lesion sizes increased exponentially from 3 to 24months of age (r=0.92, p=0.0001) and were correlated with mtROS across the age range (r=0.81, p=0.0001). Thus, LDLr-/- mice develop spontaneous diet-independent atherosclerosis, that advances exponentially with ageing. We propose that age related increases in mtROS contribute to accelerate atherosclerosis development in hypercholesterolemic mice. © 2017 Elsevier Inc

Mangifera Indica L. Extract (vimang®) And Its Main Polyphenol Mangiferin Prevent Mitochondrial Oxidative Stress In Atherosclerosis-prone Hypercholesterolemic Mouse

Atherosclerosis is linked to a number of oxidative events ranging from low-density lipoprotein (LDL) oxidation to the increased production of intracellular reactive oxygen species (ROS). We have recently demonstrated that liver mitochondria isolated from the atherosclerosis-prone hypercholesterolemic LDL receptor knockout (LDLr-/-) mice have lower content of NADP(H)-linked substrates than the controls and, as consequence, higher sensitivity to oxidative stress and mitochondrial membrane permeability transition (MPT). In the present work, we show that oral supplementation with the antioxidants Mangifera indica L. extract (Vimang®) or its main polyphenol mangiferin shifted the sensitivity of LDLr-/- liver mitochondria to MPT to control levels. These in vivo treatments with Vimang® and mangiferin also significantly reduced ROS generation by both isolated LDLr-/- liver mitochondria and spleen lymphocytes. In addition, these antioxidant treatments prevented mitochondrial NAD(P)H-linked substrates depletion and NADPH spontaneous oxidation. In summary, Vimang® and mangiferin spared the endogenous reducing equivalents (NADPH) in LDLr-/- mice mitochondria correcting their lower antioxidant capacity and restoring the organelle redox homeostasis. The effective bioavailability of these compounds makes them suitable antioxidants with potential use in atherosclerosis susceptible conditions. © 2008 Elsevier Ltd. 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(Vimang) protection against serum oxidative stress in elderly humans (2006) Arch Med Res, 37, pp. 158-164Nunez-Selles, A.J., Velez-Castro, H.T., Aguero-Aguero, J., Gonzalez-Gonzalez, J., Naddeo, F., De Simone, F., Isolation and quantitative analysis of phenolic antioxidants, free sugars, and polyols from mango (Mangifera indica L.) stem bark aqueous decoction used in Cuba as nutritional supplement (2002) J Agric Food Chem, 50, pp. 762-766Andreu, G.L., Delgado, R., Velho, J.A., Curti, C., Vercesi, A.E., Iron complexing activity of mangiferin, a naturally occurring glucosylxanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate (2005) Eur J Pharmacol, 513, pp. 47-55Pardo-Andreu, G., Sánchez-Baldoquín, C., Ávila-González, R., Delgado, R., Naal, Z., Curti, C., Fe(III) improves antioxidant and cytoprotecting activities of mangiferin (2006) Eur J Pharmacol, 547, pp. 31-36Pardo-Andreu, G.L., Delgado, R., Núñez-Sellés, A.J., Vercesi, A.E., Dual mechanism of mangiferin protection against iron- induced damage to 2-deoxyribose and ascorbate oxidation (2006) Pharmacol Res, 53, pp. 253-260Kaplan, R.S., Pedersen, P.L., Characterization of phosphate efflux pathways in rat liver mitochondria (1983) Biochem J, 212, pp. 279-288Gornall, A.G., Bardawill, C.J., David, M.M., Determination of serum proteins by means of biuret reaction (1949) J Biol Chem, 177, pp. 751-766Reynafarje, B., Costa, L.E., Lehninger, A.L.J., O2 solubility in aqueous media determined by a kinetic method (1985) Anal Biochem, 145, pp. 406-418Åkerman, K.E.O., Wikstrom, M.K.F., Safranine as a probe of the mitochondrial membrane potential (1976) FEBS Lett, 68, pp. 191-197Fagian, M.M., Pereira-da-Silva, L., Martins, I.S., Vercesi, A.E., Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca 2+ plus prooxidants (1990) J Biol Chem, 265, pp. 19955-19960Boyum, A., Isolation of lymphocytes, granulocytes and macrophages (1976) Scand J Immunol, 5, pp. 9-15Votyakova, T.V., Reynolds, I.J., DeltaPsi(m)-dependent and -independent production of reactive oxygen species by rat brain mitochondria (2001) J Neurochem, 79, pp. 266-277Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Fernandez-Checa, J.C., Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. 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Mitochondrial Atp-sensitive K+ Channels As Redox Signals To Liver Mitochondria In Response To Hypertriglyceridemia

We have recently demonstrated that hypertriglyceridemic (HTG) mice present both elevated body metabolic rates and mild mitochondrial uncoupling in the liver owing to stimulated activity of the ATP-sensitive potassium channel (mitoKATP). Because lipid excess normally leads to cell redox imbalance, we examined the hepatic oxidative status in this model. Cell redox imbalance was evidenced by increased total levels of carbonylated proteins, malondialdehydes, and GSSG/GSH ratios in HTG livers compared to wild type. In addition, the activities of the extramitochondrial enzymes NADPH oxidase and xanthine oxidase were elevated in HTG livers. In contrast, Mn-superoxide dismutase activity and content, a mitochondrial matrix marker, were significantly decreased in HTG livers. Isolated HTG liver mitochondria presented lower rates of H2O2 production, which were reversed by mitoKATP antagonists. In vivo antioxidant treatment with N-acetylcysteine decreased both mitoKATP activity and metabolic rates in HTG mice. These data indicate that high levels of triglycerides increase reactive oxygen generation by extramitochondrial enzymes that promote mitoKATP activation. The mild uncoupling mediated by mitoKATP increases metabolic rates and protects mitochondria against oxidative damage. Therefore, a biological role for mitoKATP as a redox sensor is shown here for the first time in an in vivo model of systemic and cellular lipid excess. © 2009 Elsevier Inc. 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Thermal comfort index and infrared temperatures for lambs subjected to different environmental conditions

There is an abundance of thermal indices with different input parameters and applicabilities. Infrared thermography is a promising technique for evaluating the response of animals to the environment and differentiating between genetic groups. Thus, the aim of this study was to evaluate superficial body temperatures of lambs from three genetic groups under different environmental conditions, correlating these with thermal comfort indices. Forty lambs (18 males and 22 females) from three genetic groups (Santa Inês, Ile de France × Santa Inês and Dorper × Santa Inês) were exposed to three climatic conditions: open air, housed and artificial heating. Infrared thermal images were taken weekly at 6h, 12h and 21h at the neck, front flank, rear flank, rump, nose, skull, trunk and eye. Four thermal comfort indices were calculated using environmental measurements including black globe temperature, air humidity and wind speed. Artificial warming, provided by infrared lamps and wind protection, conserved and increased the superficial body temperature of the lambs, thus providing lower daily thermal ranges. Artificial warming did not influence daily weight gain or mortality. Skin temperatures increased along with increases in climatic indices. Again, infrared thermography is a promising technique for evaluating thermal stress conditions and differentiating environments. However, the use of thermal imaging for understanding animal responses to environmental conditions requires further study