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- 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.
- 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.