Browsing by Subject "Cardiotoxicity"

Now showing 1 - 9 of 9
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    Acute cardiotoxicity induced by doxorubicin in right ventricle is associated with increase of oxidative stress and apoptosis in rats
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Anghel, N.; Herman, H.; Balta, C.; Rosu, M.; Stan, M.S.; Nita, D.; Ivan, A.; Galajda, Z.; Ardelean, A.; Dinischiotu, A.; Hermenean, A.
    Doxorubicin (DOX) is one of the most effective chemotherapeutic agents, but its efficiency is seriously limited by the risk of developing cardiomyopathy. The most recognized cardiotoxic effect is left ventricular (LF) dysfunction, but MRI and echocardiography data demonstrated significant right ventricle (RV) function impairment. In order to clarify this aspect, the present study investigated the potential of DOX to induce acute RV cardiotoxicity at the same time as LV impairment. Rats were intraperitoneally (i.p.) injected with a single dose of 15 mg/kg DOX. DOXtreated rats were characterized by decreased body and heart weights, elevated levels of creatine kinase (CKMB) and lactate dehydrogenase (LDH) activities compared to controls. Biochemical analyses on RV tissue revealed that the level of malondialdehyde (MDA) was significant increased (p<0.05) and activities of catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPX) antioxidant enzymes were decreased by 13%, 27% and 18%, respectively, compared to control. Histopathogical and electron microscopic studies revealed DOX-induced damage in both ventricles and an increase of interstitial collagen fibers compared to controls (p<0.001), whereas immunohistochemical analysis showed weak and irregular desmin expression. Furthermore, mitochondrion-induced apoptotic pathways were also activated in both ventricles, as reflected by the up-regulation of Bax/Bcl-2 mRNA expression ratio (p<0.001) and increase of Bax and caspase-3 protein expression, as well as by the significant elevation of TUNEL positive nuclei, compared to controls (p<0.001). The results showed that DOX exerted RV toxic effects at the same time as those reported in the LV, which might be mediated through the mitochondrial-dependent apoptosis.
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    Chrysin attenuates cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2015) Anghe, N.; Cotoraci, C.; Ivan, A.; Suciu, M.; Herman, H.; Balta, C.; Nicolescu, L.; Olariu, T.; Galajda, Z.; Ardelean, A.; Hermenean, A.
    y. Chrysin (CHR) is a natural flavonoid and is present in high concentration in honey, propolis and many plant extracts. The aim of the present study was to evaluate the effects of CHR to reduce cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity. Morphology of the cardiomyocytes was determined by optic and transmission electron microscopy and biochemistry methods. The expression of Bcl-2, Bax and Caspase-3 were assessed by immunofluorecence. Tunel assay was used to assess apoptosis in cardiomyocytes. In addition, the distribution of desmin protein was evaluated using immunohistochemistry. Our results show that MTX treatment significantly increased serum levels of creatine kinase isoenzyme (CK-MB), indicator of cardiac injury and withdrawn under CHR protection. Expression levels of Bcl-2 decreased, while those of Bax and caspase-3 increased following MTX treatment. 50 mg/kg of daily CHR intake reduced Bax and caspase-3 immunopositivity and restored Bcl-2 levels to a value comparable to the control. TUNEL (+) cardiomyocyte nuclei of MTX group showed typical signs of apoptosis which almost completely disappeared in response to 50 mg/kg CHR treatment. In parallel, an irregular distribution and a weak expression of desmin is associated with MTX induced cardiotoxic effects which was also restored by CHR treatment. In conclusion chrysin inhibits MTX-triggered cardiomyocyte apoptosis via multiple pathways, including decrease of the Bax/Bcl-2 ratio and caspase-3 expression along with preservation of the desmin disarray.
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    Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes
    (2016) Asensio Lopez, Maria del Carmen; Soler, Fernando; Sanchez Mas, Jesus; Pascual Figal, Domingo A.; Fernandez Belda, Francisco; Lax Pérez, Antonio Manuel; Medicina
    In atrial-derived HL-1 cells, ryanodine receptor and Naþ/Ca2þ-exchanger were altered early by 5 mM doxorubicin. The observed effects were an increase of cytosolic Ca2þ at rest, ensuing ryanodine receptor phosphorylation, and the slowing of Ca2þ transient decay after caffeine addition. Doxorubicin triggered a linear rise of reactive oxygen species (ROS) with no early effect on mitochondrial inner membrane potential. Doxorubicin and ROS were both detected in mitochondria by colocalization with fluorescence probes and doxorubicin-induced ROS was totally blocked by mitoTEMPO. The NADPH oxidase activity in the mitochondrial fraction was sensitive to inhibition by GKT137831, and doxorubicin-induced ROS decreased gradually as the GKT137831 concentration added in preincubation was increased. When doxorubicin-induced ROS was prevented by GKT137831, the kinetic response revealed a permanent degree of protection that was consistent with mitochondrial NADPH oxidase inhibition. In contrast, the ROS induction by doxorubicin after melatonin preincubation was totally eliminated at first but the effect was completely reversed with time. Limiting the source of ROS production is a better alternative for dealing with oxidative damage than using ROS scavengers. The short-term effect of doxorubicin on Ca2þ transporters involved in myocardiac contractility was dependent on oxidative damage, and so the impairment was subsequent to ROS production.
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    Experimental study design: gene silencing model using siRNAs in mice with cardiotoxicity.
    Lax Pérez, Antonio Manuel; Asensio López, Maria del Carmen; Medicina
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    Ferritin heavy chain as main mediator of preventive effect of metformin against mitochondrial damage induced by doxorubicin in cardiomyocytes
    (2014-02) Asensio Lopez, Maria del Carmen; Sanchez Mas, Jesus; Pascual Figal, Domingo A.; de la Torre, Carlos; Valdes, Mariano; Lax Pérez, Antonio Manuel; Medicina
    The efficacy of doxorubicin (DOX) as an antitumor agent is greatly limited by the induction of cardiomyopathy, which results from mitochondrial dysfunction and iron-catalyzed oxidative stress in the cardiomyocyte. Metformin (MET) has been seen to have a protective effect against the oxidative stress induced by DOX in cardiomyocytes through its modulation of ferritin heavy chain (FHC), the main iron-storage protein. This study aimed to assess the involvement of FHC as a pivotal molecule in the mitochondrial protection offered by MET against DOX cardiotoxicity. The addition of DOX to adult mouse cardiomyocytes (HL-1 cell line) increased the cytosolic and mitochondrial free iron pools in a time-dependent manner. Simultaneously, DOX inhibited complex I activity and ATP generation and induced the loss of mitochondrial membrane potential. The mitochondrial dysfunction induced by DOX was associated with the release of cytochrome c to the cytosol, the activation of caspase 3, and DNA fragmentation. The loss of iron homeostasis, mitochondrial dysfunction, and apoptosis induced by DOX were prevented by treatment with MET 24h before the addition of DOX. The involvement of FHC and NF-κB was determined through siRNA-mediated knockdown. Interestingly, the presilencing of FHC or NF-κB with specific siRNAs blocked the protective effect induced by MET against DOX cardiotoxicity. These findings were confirmed in isolated primary neonatal rat cardiomyocytes. In conclusion, these results deepen our knowledge of the protective action of MET against DOX-induced cardiotoxicity and suggest that therapeutic strategies based on FHC modulation could protect cardiomyocytes from the mitochondrial damage induced by DOX by restoring iron homeostasis
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    Involvement of ferritin heavy chain in the preventive effect of metformin against doxorubicin-induced cardiotoxicity
    (Elsevier, 2013-04) Asensio López, Maria del Carmen; Sánchez Mas, Jesús; Pascual Figal, Domingo A; Abenza, Sergio; Perez Martinez, Maria T; Valdés, Mariano; Lax Pérez, Antonio Manuel; Medicina
    Doxorubicin is a wide-spectrum chemotherapeutic agent, although a cumulative dose may cause cardiac damage and lead to heart failure. Doxorubicin cardiotoxicity is dependent on the intracellular iron pool and manifests itself by increasing oxidative stress. Our group has recently shown the ability of metformin, an oral antidiabetic with cardiovascular benefits, to protect cardiomyocytes from doxorubicin-induced damage. This work aimed to study whether metformin is able to modulate the expression of ferritin, the major intracellular iron storage protein, in cardiomyocytes and whether it is involved in their protection. The addition of metformin to adult mouse cardiomyocytes (HL-1 cell line) induced both gene and protein expression of the ferritin heavy chain (FHC) in a time-dependent manner. The silencing of FHC expression with siRNAs inhibited the ability of metformin to protect cardiomyocytes from doxorubicin-induced damage, in terms of the percentage of cell viability, the levels of reactive oxygen species, and the activity of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase). In addition, metformin induced the activation of NF-κB in HL-1 cells, whereas preincubation with SN50, an inhibitor of NF-κB, blocked the upregulation of the FHC and the protective effect mediated by metformin. Taken together, these results provide new knowledge on the protective actions of metformin against doxorubicin-induced cardiotoxicity by identifying FHC and NF-κB as the major mediators of this beneficial effect.
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    Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system
    (Elsevier, 2011-11-15) Asensio López, María del Carmen; Lax Pérez, Antonio Manuel; Pascual Figal, Domingo A; Valdés, Mariano; Sánchez Mas, Jesús; Medicina
    Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. Metformin exerts cardioprotective actions via AMP-activated protein kinase (AMPK) and increases the expression of adiponectin and its receptors (adipoR1 and adipoR2) in skeletal muscle and adipose tissue, but its effect on cardiac tissue is still unknown. This work aimed to study whether metformin exerts any protective action against the cardiotoxicity of doxorubicin and whether the cardiac system of adiponectin is involved in any such action. The addition of doxorubicin (5μM) to adult mouse cardiomyocytes (HL-1 cell line) induced apoptosis, which was characterized by a loss of cell viability, activation of caspases, and fragmentation of the genetic material. Doxorubicin treatment also caused a decrease in the activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase. Pretreatment with metformin (4mM, 24h) provided protection against doxorubicin-induced damage. This pretreatment significantly increased cell viability, attenuated the activation of caspases and the fragmentation of genetic material, and restored the antioxidant activity. In addition, metformin up-regulated the expression of adiponectin and its receptors, adipoR1 and adipoR2, in cardiomyocytes. In contrast, silencing either adipoR1 or adipoR2 with siRNA inhibited the AMPK activation and the protective effects of metformin. Taken together, these results demonstrate that metformin protects cardiomyocytes from doxorubicin-induced damage and that the cardiac adiponectin system plays an important role in this protective action.
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    Soluble sST2 isoform is related to cardiotoxicity
    (2023-07-19) Lax Pérez, Antonio Manuel; Asensio López, Maria del Carmen; Medicina