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- Vanadium distribution, lipid peroxidation and oxidative stress markers upon decavanadate in vivo administrationPublication . S. Soares, Sandra; Martins, H.; Duarte, Rui O.; Moura, José J. G.; Coucelo, Josefina; Gutiérrez-Merino, Carlos; Aureliano, M.The contribution of decameric vanadate species to vanadate toxic effects in cardiac muscle was studied following an intravenous administration of a decavanadate solution (1 mM total vanadium) in Sparus aurata. Although decameric vanadate is unstable in the assay medium, it decomposes with a half-life time of 16 allowing studying its effects not only in vitro but also in vivo. After 1, 6 and 12 h upon decavanadate administration the increase of vanadium in blood plasma, red blood cells and in cardiac mitochondria and cytosol is not affected in comparison to the administration of a metavanadate solution containing labile oxovanadates. Cardiac tissue lipid peroxidation increases up to 20%, 1, 6 and 12 h after metavanadate administration, whilst for decavanadate no effects were observed except 1 h after treatment (+20%). Metavanadate administration clearly differs from decavanadate by enhancing, 12 h after exposure, mitochondrial superoxide dismutase (SOD) activity (+115%) and not affecting catalase (CAT) activity whereas decavanadate increases SOD activity by 20% and decreases ( 55%) mitochondrial CAT activity. At early times of exposure, 1 and 6 h, the only effect observed upon decavanadate administration was the increase by 20% of SOD activity. In conclusion, decavanadate has a different response pattern of lipid peroxidation and oxidative stress markers, in spite of the same vanadium distribution in cardiac cells observed after decavanadate and metavanadate administration. It is suggested that once formed decameric vanadate species has a different reactivity than vanadate, thus, pointing out that the differential contribution of vanadium oligomers should be taken into account to rationalize in vivo vanadate toxicity.
- Decavanadate toxicity effects following in vivo administrationPublication . S. Soares, Sandra; Gutiérrez-Merino, Carlos; Aureliano, M.Very few in vivo animal studies involving vanadium consider the contribution of decavanadate (V10) to vanadium biological effects. Recently, it is been suggested that decameric vanadate may not completely fall apart into other vanadate oligomers before induces changes in cell homeostasis, namely in several stress markers. An acute exposure of different fish species (Halobactrachus didactilus, Lusitanian toadfish, and Sparus aurata, gilthead seabream) to decavanadate, but not to other vanadate oligomers, induced different effects than vanadate in catalase activity, glutathione content, lipid peroxidation, mitochondrial superoxide anion production and vanadium accumulation, whereas both solutions seem to equally depress reactive oxygen species (ROS) production as well as total intracellular reducing power. Vanadium is accumulated in Sparus aurata mitochondria in particular when decavanadate is administrated. Moreover, exposure to different vanadate oligomers induced morphological changes in fish cardiac, hepatic and renal tissues causing tissues lesions in the liver and kidney, but not cardiac tissue. Nevertheless, the results highlight that different vanadate oligomers seem to follow, not only in vitro but also in vivo, different pathways, with different targets and effects. These recent findings, that are now summarized, point out the decameric vanadate species contributions to in vivo effects induced by vanadium in biological systems.
- Vanadate oligomers: in vivo effects in hepatic vanadium accumulation and stress markersPublication . Gândara, Ricardo M. C.; S. Soares, Sandra; Martins, H.; Gutiérrez-Merino, Carlos; Aureliano, M.The formation of vanadate oligomeric species is often disregarded in studies on vanadate effects in biological systems, particularly in vivo, even though they may interact with high affinity with many proteins. We report the effects in fish hepatic tissue of an acute intravenous exposure (12, 24 h and 7 days) to two vanadium(V) solutions, metavanadate and decavanadate, containing different vanadate oligomers administered at sub-lethal concentration (5 mM; 1 mg/kg). Decavanadate solution promotes a 5-fold increase (0.135 ± 0.053 lg V 1 dry tissues) in the vanadium content of the mitochondrial fraction 7 days after exposition, whereas no effects were observed after metavanadate solution administration. Reduced glutathione (GSH) levels did not change and the overall reactive oxygen species (ROS) production was decreased by 30% 24 h after decavanadate administration, while for metavanadate, GSH levels increased 35%, the overall ROS production was depressed by 40% and mitochondrial superoxide anion production decreased 45%. Decavanadate intoxication did not induce changes in the rate of lipid peroxidation till 12 h, but later increased 80%, which is similar to the increase observed for metavanadate after 24 h. Decameric vanadate administration clearly induces different effects than the other vanadate oligomeric species, pointing out the importance of taking into account the different vanadate oligomers in the evaluation of vanadium(V) effects in biological systems.
- The pathways of cell death in cardiomyocytes induced by vanadatePublication . Aureliano, M.; S. Soares, Sandra; Henao, Fernando; Gutiérrez-Merino, CarlosAfter 24 hours, cardiac myocytes exposure to 10 μM (LD50) vanadate (meta or decavanadate) an increased (30%) of caspase 3-activation was observed, although not significant. On contrary, a significant decrease (40%) of ATP content, characteristic of necrotic cell death was detected. Furthermore, vanadate treatment increased intracellular Ca2+ level from 60 nM to 240 nM, whereas it decreases mitochondria superoxide anion generation and induces mitochondria membrane depolarization (IC50=6.5 μM). In conclusion, micromolar vanadate exposure induces large chances in two major bioenergetic markers in cardiac myocytes: intracellular calcium concentration and superoxide anion mitochondrial production, suggesting a necrotic cell death through a mitochondrial toxic pathway.
- Mitochondria as a target for decavanadate toxicity in Sparus aurata heartPublication . S. Soares, Sandra; Gutiérrez-Merino, Carlos; Aureliano, M.In a previous in vivo study we have reported that vanadium distribution, antioxidant enzymes activity and lipid peroxidation in Sparus aurata heart are strongly dependent on the oligomeric vanadate species being administered. Moreover, it was suggested that vanadium is accumulated in mitochondria, in particular when V10 was intravenously injected. In this work we have done a comparative study of the effects of V10 and monomeric vanadate (V1) on cardiac mitochondria from S. aurata. V10 inhibits mitochondrial oxygen consumption with an IC50 of 400 nM, while the IC50 for V1 is 23 M. V10 also induced mitochondrial depolarization at very low concentrations, with an IC50 of 196 nM, and 55 Mof V1was required to induce the same effect. Additionally, up to 5 M V10 did inhibit neither F0F1-ATPase activity nor NADH levels and it did not affect respiratory complexes I and II, but it induced changes in the redox steady-state of complex III. It is concluded that V10 inhibits mitochondrial oxygen consumption and induces membrane depolarization more strongly than V1, pointing out that mitochondria is a toxicological target for V10 and the importance to take into account the contribution of V10 to the vanadate toxic effects.
- Vanadate induces necrotic cell death in neonatal rat cardiomyocytes through mitochondrial membrane depolarizationPublication . S. Soares, Sandra; Henao, Fernando; Aureliano, M.; Gutiérrez-Merino, CarlosBesides the well-known inotropic effects of vanadium in cardiac muscle, previous studies have shown that vanadate can stimulate cell growth or induce cell death. In this work, we studied the toxicity to neonatal rat ventricular myocytes (cardiomyocytes) of two vanadate solutions containing different oligovanadates distribution, decavanadate (containing decameric vanadate, V10) and metavanadate (containing monomeric vanadate and also di-, tetra-, and pentavanadate). Incubation for 24 h with decavanadate or metavanadate induced necrotic cell death of cardiomyocytes, without significant caspase-3 activation. Only 10 μM total vanadium of either decavanadate (1 μMV10) or metavanadate (10 μM total vanadium) was needed to produce 50% loss of cell viability after 24 h (assessed with MTT and propidium iodide assays). Atomic absorption spectroscopy showed that vanadium accumulation in cardiomyocytes after 24 h was the same when incubation was done with decavanadate or metavanadate. A decrease of 75% of the rate of mitochondrial superoxide anion generation, monitored with dihydroethidium, and a sustained rise of cytosolic calcium (monitored with Fura-2-loaded cardiomyocytes) was observed after 24 h of incubation of cardiomyocytes with decavanadate or metavanadate concentrations close to those inducing 50% loss of cell viability produced. In addition, mitochondrial membrane depolarization within cardiomyocytes, monitored with tetramethylrhodamine ethyl esther or with 3,3′,6,6′-tetrachloro-1,1′,3,3′- tetraethylbenzimidazolcarbocyanine iodide, were observed after only 6 h of incubation with decavanadate or metavanadate. The concentration needed for 50% mitochondrial depolarization was 6.5 ( 1 μM total vanadium for both decavanadate (0.65 μMV10) and metavanadate. In conclusion, mitochondrial membrane depolarization was an early event in decavanadate- and monovanadate-induced necrotic cell death of cardiomyocytes.
- Vanadium and cadmium in vivo effects in cardiac muscle: metal accumulation and oxidative stress markersPublication . S. Soares, Sandra; Martins, H.; Gutiérrez-Merino, Carlos; Aureliano, M.Several biological studies associate vanadium and cadmium with the production of reactive oxygen species (ROS), leading to lipid peroxidation and antioxidant enzymes alterations. The present study aims to analyse and compare the oxidative stress responses induced by an acute intravenous exposure (1 and 7 days) to a sub-lethal concentration (5 mM) of two vanadium solutions, containing different vanadate noligomers (n=1–5 or n=10), and a cadmium solution on the cardiac muscle of the marine teleost Halobatrachus didactylus (Lusitanian toadfish). It was observed that vanadium is mainly accumulated in mitochondria (1.33±0.26 μM), primarily when this element was administrated as decameric vanadate, than when administrated as metavanadate (432±294 nM), while the highest content of cadmium was found in cytosol (365±231 nM). Indeed, decavanadate solution promotes stronger increases in mitochondrial antioxidant enzymes activities (catalase: +120%; superoxide dismutase: +140%) than metavanadate solution. On contrary, cadmium increases cytosolic catalase (+111%) and glutathione peroxidases (+50%) activities. It is also observed that vanadate oligomers induce in vitro prooxidant effects in toadfish heart, with stronger effects induced by metavanadate solution. In summary, vanadate and cadmium are differently accumulated in blood and cardiac subcellular fractions and induced different responses in enzymatic antioxidant defence mechanisms. In the present study, it is described for the first time the effects of equal doses of two different metals intravenously injected in the same fish species and upon the same exposure period allowing to understand the mechanisms of vanadate and cadmium toxicity in fish cardiac muscle.