Carmen Herencia

University of Cordoba (Spain), Cordoue, Andalusia, Spain

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Publications (19)67.09 Total impact

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    ABSTRACT: Clinical and epidemiologic studies reveal an association between vitamin D deficiency and increased risk of cardiovascular disease. Because vascular smooth muscle cell (VSMC)-derived tissue factor (TF) is suggested to be critical for arterial thrombosis, we investigated whether the vitamin D molecules calcitriol and paricalcitol could reduce the expression of TF induced by the proinflammatory cytokine TNF-α in human aortic VSMCs. We found that, compared with controls, incubation with TNF-α increased TF expression and procoagulant activity in a NF-κB-dependent manner, as deduced from the increased nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells protein 65 (p65-NF-κB) and direct interaction of NF-κB to the TF promoter. This was accompanied by the up-regulation of TF signaling mediator protease-activated receptor 2 (PAR-2) expression and by the down-regulation of vitamin D receptor expression in a miR-346-dependent way. However, addition of calcitriol or paricalcitol blunted the TNF-α-induced TF expression and activity (2.01 ± 0.24 and 1.32 ± 0.14 vs. 3.02 ± 0.39 pmol/mg protein, P < 0.05), which was associated with down-regulation of NF-κB signaling and PAR-2 expression, as well as with restored levels of vitamin D receptor and enhanced expression of TF pathway inhibitor. Our data suggest that inflammation promotes a prothrombotic state through the up-regulation of TF function in VSMCs and that the beneficial cardiovascular effects of vitamin D may be partially due to decreases in TF expression and its activity in VSMCs.-Martinez-Moreno, J. M., Herencia, C., Montes de Oca, A., Muñoz-Castañeda, J. R., Rodríguez-Ortiz, M. E., Díaz-Tocados, J. M., Peralbo-Santaella, E., Camargo, A., Canalejo, A., Rodriguez, M., Velasco-Gimena, F., Almaden, Y. Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells.
    No preview · Article · Dec 2015 · The FASEB Journal
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    Full-text · Dataset · Dec 2015
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    ABSTRACT: Background Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). Low magnesium levels are associated with VC and recent in vitro studies confirm a protective role of magnesium, which is mediated by its entry into the VSMCs through the Transient Receptor Potential Melastatin 7 (TRPM7) channel. The role of Angiotensin II (Ang II) on VC is still unclear. Since Ang II is able to stimulate TRPM7 activity, we hypothesize that it might prevent VC. Thus, the aim of this study was to dissect the direct effect of Ang II on VC.Materials and methodsWe worked with a model of high phosphate (HP)-induced calcification in human aortic smooth muscle cells, which resembles the CKD-related VC.ResultsAddition of Ang II to cells growing in HP decreased calcification, which was associated with the up-regulation of the osteogenic factors BMP2, Runx2/Cbfa1, Osterix and ALP. A reduction of magnesium entry into the HP-calcifying cells was found. The treatment with Ang II avoided this reduction, which was reversed by the co-treatment with the TRPM7-inhibitor 2-APB. The protective effect of Ang II was related to AT1R-induced ERK1/2 MAPKinase activation. HP-induced calcification was also associated with the upregulation of the canonical Wnt/beta-catenin pathway, while its downregulation was related to attenuation of calcification by Ang II.Conclusionas hypothesized, Ang II prevented phosphate-induced calcification in VSMCs, which appears mediated by the increase of magnesium influx and by the activation of the ERK1/2 and the inhibition of the canonical Wnt/beta-catenin signaling pathwaysThis article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · European Journal of Clinical Investigation
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    ABSTRACT: It is unknown if the beneficial effects of mesenchymal stromal cells (MSC) transplantation into the liver are dependent on their anchorage and differentiation into hepatocytes or rather the result of the release of stem cell intracellular content with hepatoprotector properties. The effects of intact MSC transplantation were compared with the infusion of MSC lysates in an experimental rat model of acute liver failure. A more powerful hepatoprotective and antiapoptotic effect was obtained after infusion of MSC lysates than intact MSC. Changes in IL-6 levels and miRNAs might explain the beneficial effects of MSC lysates. Infusion of MSC lysates show a better hepatoprotective effect than the transplantation of intact MSC.
    Full-text · Article · Jan 2015 · Regenerative Medicine
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    ABSTRACT: Background: Cardiotrophin-1 (CT1) has been used to prevent cell death in different models of liver injury in rats. D-galactosamine induces cell death in culture rat and human hepatocytes. The present study evaluated the cytoprotective effects of CT1 in an experimental model of apoptosis induced by D-galactosamine in hepatocytes. Methods: DNA fragmentation, calpain activity and Western blots of caspase-3, calpastatin and Stat3, and Akt phosphorylation were measured. Stat3 and Akt inhibitors were used to analyze the mechanisms of action of CT1. Results: CT1 caused an increase in Stat3 and Akt phosphorylation and a decrease of DNA fragmentation, calpain activity, and caspase-3 induced by D-galactosamine. The reduction of calpain activity by CT1 was associated with an increase of calpastatin (its endogenous inhibitor). The effects of CT1 were also dependent on the activation of Sta3 or Akt. Conclusions: CT1 decreases cell death through a mechanism related to Stat3 and Akt phosphorylation and activation of calpastatin in D-galactosamine-treated hepatocytes.
    No preview · Article · Jul 2014 · Journal of Surgical Research

  • No preview · Article · Jun 2014 · PLoS ONE
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    ABSTRACT: Background Spondyloarthropathies are a group of chronic inflammatory diseases characterized by progressive new bone formation leading to ankylosis and functional disability. TNF antagonists are effective and safe long-term treatments in patients with spondyloarthropathies with inadequate response to NSAIDS. However, the beneficial effects of anti-TNF therapies on radiological evolution of these patients have not yet been demonstrated. Paricalcitol, a synthetic form of vitamin D, diminishes the calcification. It has been shown that plasma levels of vitamin D are reduced in patients with ankylosing spondylitis (AS) which inversely correlated with their inflammatory status Objectives To evaluate the effect of anti-TNF, paricalcitol and the combined treatment of both compounds on inflammatory and osteogenic differentiation processes of mesenchymal stem cells Methods Mesenchymal stem cells were obtained from bone marrow of healthy donors and differentiated into osteoblasts using dexamethasone, b-glycerophosphate and ascorbic acid. Alkaline phosphatase (AP) activity and alizarin red staining were used as differentiation and mineralization markers at 7, 14 and 21 days. After 14 days of differentiation, infliximab (100μM), paricalcitol (3x10–8M and 3x10–10M) and the combined treatments of both compounds were added to cell cultures and maintained during 7 days. Markers of new bone formation (BMP-2, osteocalcin, Runx2, osterix, AP), inflammation (IL-1b, IL-6, IL-8, IL-23, MCP-1, TGFb y VEGF) and intracellular signaling molecules (STAT3) were determined by RT-PCR and Western-blot. Wnt/b-catenin pathway regulation was evaluated by Western-blot of phosphorylated and total protein and RT-PCR of Wnt and Dkk1 Results An increase in AP activity and alizarin red staining after 21 days of treatment was observed. The gene expression of several osteogenic genes (i.e. BMP-2 and Runx2) was significantly elevated. Osteogenic differentiation further promoted an increase in the gene expression of cytokines/chemokines (i.e. IL-1b, IL-6, IL-8, IL-23, MCP-1, TGF1b) and regulatory molecules (STAT3). Paricalcitol and anti-TNF treatment produced a significant reduction of inflammatory profile present in osteoblasts. Yet, none treatment modulated the osteogenic process. A reduction in STAT3 activity by effect of anti-TNF and paricalcitol was observed, which was parallel to the decreased gene expression of inflammatory cytokines. None treatment promoted variations in b-catenin expression, suggesting that this molecule is not involved in the bone formation process. The combined treatment did not alter the gene expression profiles in relation to each treatment given alone Conclusions 1) Paricalcitol promotes an inhibition of inflammatory profile in osteoblast cells similar to anti-TNF treatment. 2) After osteoblast differentiation, this process is not reverted by anti-TNF or paricalcitol treatment. Thus, paricalcitol might prevent the vitamin D deficiency demonstrated in patients with AS, thereby contributing to the reduction of the inflammatory status and the prevention of osteoporosis, a concominant symptom of bone damage in patients with AS Acknowledgements Supported by JA PI-0314-2012 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5076
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Introduction and Aims: In clinical practice it has been reported that hypomagnesaemia is associated to low mineral density. On the other hand in vitro studies have shown that magnesium (Mg) decreases calcification in vascular smooth muscle cells. But the effects of increasing Mg levels on bone homeostasis are poorly understood. Here we elucidate the effects of elevated Mg on the osteogenic differentiation of rat MSC and hence on bone metabolism. Methods: MSC were differentiated to osteoblasts by incubation with dexamethasone, β-glycerol phosphate and ascorbic acid at different Mg concentrations. Mineralization capacity and osteoblastic markers were measured. Involvement of canonical Wnt and Notch signaling pathways in this process was analyzed by immunofluorescence. Inhibition of Mg channel TRPM7 with 2-aminoethoxydiphenyl borate (2-APB) was also studied. Results: Elevated Mg increases matrix mineralization, alkaline phosphatase activity and FGF-23 production in rat MSC. Further, the expression of osteoblast master genes such as Runx2, Osterix and Osteocalcin was augmented (Table 1). No significant differences on nuclear translocation of β-catenin were observed. However, translocation of Notch1 intracellular domain (NICD) into the nuclei increased significantly in osteoblasts cultured with rising Mg concentrations. Further, Mg promoted proliferation indicated by increasing CyclinD1 and PCNA levels. 2-APB administration decreased nuclear NICD, alkaline phosphatase activity, osteoblast master genes and proliferation marker expression. Conclusions: Our data strongly suggest that Mg directly enhances osteogenesis in rat MSC. View larger version: In this window In a new window Download as PowerPoint Slide
    Full-text · Article · May 2014 · Nephrology Dialysis Transplantation
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    ABSTRACT: Transforming growth factor-β (TGF-β) is a key cytokine during differentiation of mesenchymal stem cells (MSC) into vascular smooth muscle cells (VSMC). High phosphate induces a phenotypic transformation of vascular smooth muscle cells (VSMC) into osteogenic-like cells. This study was aimed to evaluate signaling pathways involved during VSMC differentiation of MSC in presence or not of high phosphate. Our results showed that TGF-β induced nuclear translocation of Smad3 as well as the expression of vascular smooth muscle markers, such as smooth muscle alpha actin, SM22α, myocardin, and smooth muscle-myosin heavy chain. The addition of high phosphate to MSC promoted nuclear translocation of Smad1/5/8 and the activation of canonical Wnt/β-catenin in addition to an increase in BMP-2 expression, calcium deposition and alkaline phosphatase activity. The administration of TGF-β to MSC treated with high phosphate abolished all these effects by inhibiting canonical Wnt, BMP and TGF-β pathways. A similar outcome was observed in high phosphate-treated cells after the inhibition of canonical Wnt signaling with Dkk-1. Conversely, addition of both Wnt/β-catenin activators CHIR98014 and lithium chloride enhanced the effect of high phosphate on BMP-2, calcium deposition and alkaline phosphatase activity. Full VSMC differentiation induced by TGF-β may not be achieved when extracellular phosphate levels are high. Moreover, TGF-β prevents high phosphate-induced osteogenesis by decreasing the nuclear translocation of Smad 1/5/8 and avoiding the activation of Wnt/β-catenin pathway.
    Full-text · Article · Feb 2014 · PLoS ONE
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    ABSTRACT: Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved.
    Full-text · Article · Feb 2014 · PLoS ONE
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    ABSTRACT: The interest on magnesium (Mg) has grown since clinical studies have shown the efficacy of Mg-containing phosphate binders. However, some concern has arisen for the potential effect of increased serum Mg on parathyroid hormone (PTH) secretion. Our objective was to evaluate the direct effect of Mg in the regulation of the parathyroid function; specifically, PTH secretion and the expression of parathyroid cell receptors: CaR, the vitamin D receptor (VDR) and FGFR1/Klotho. The work was performed in vitro by incubating intact rat parathyroid glands in different calcium (Ca) and Mg concentrations. Increasing Mg concentrations from 0.5 to 2 mM produced a left shift of PTH-Ca curves. With Mg 5 mM, the secretory response was practically abolished. Mg was able to reduce PTH only if parathyroid glands were exposed to moderately low Ca concentrations; with normal-high Ca concentrations, the effect of Mg on PTH inhibition was minor or absent. After 6-h incubation at a Ca concentration of 1.0 mM, the expression of parathyroid CaR, VDR, FGFR1 and Klotho (at mRNA and protein levels) was increased with a Mg concentration of 2.0 when compared with 0.5 mM. Mg reduces PTH secretion mainly when a moderate low calcium concentration is present; Mg also modulates parathyroid glands function through upregulation of the key cellular receptors CaR, VDR and FGF23/Klotho system.
    Full-text · Article · Oct 2013 · Nephrology Dialysis Transplantation
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    ABSTRACT: The present study investigates the differential effect of two vitamin D receptor agonists, calcitriol and paricalcitol, on human aortic smooth muscle cells calcification in vitro. Human vascular smooth muscle cells were incubated in a high phosphate (HP) medium alone or supplemented with either calcitriol 10(-8)M (HP + CTR) or paricalcitol 3·10(-8) M (HP + PC). HP medium induced calcification, which was associated with the upregulation of mRNA expression of osteogenic factors such as bone morphogenetic protein 2 (BMP2), Runx2/Cbfa1, Msx2, and osteocalcin. In these cells, activation of Wnt/β-catenin signaling was evidenced by the translocation of β-catenin into the nucleus and the increase in the expression of direct target genes as cyclin D1, axin 2, and VCAN/versican. Addition of calcitriol to HP medium (HP + CTR) further increased calcification and also enhanced the expression of osteogenic factors together with a significant elevation of nuclear β-catenin levels and the expression of cyclin D1, axin 2, and VCAN. By contrast, the addition of paricalcitol (HP + PC) not only reduced calcification but also downregulated the expression of BMP2 and other osteoblastic phenotype markers as well as the levels of nuclear β-catenin and the expression of its target genes. The role of Wnt/β-catenin on phosphate- and calcitriol-induced calcification was further demonstrated by the inhibition of calcification after addition of Dickkopf-related protein 1 (DKK-1), a specific natural antagonist of the Wnt/β-catenin signaling pathway. In conclusion, the differential effect of calcitriol and paricalcitol on vascular calcification appears to be mediated by a distinct regulation of the BMP and Wnt/β-catenin signaling pathways.
    Preview · Article · Aug 2012 · AJP Renal Physiology
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    ABSTRACT: Wnt/β-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/β-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, β-catenin nuclear translocation, up-regulation of genes related to the Wnt/β-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/β-catenin inactivation. Hepatocytes with nuclear translocation of β-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase β-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin β-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/β-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.
    Full-text · Article · Apr 2012 · PLoS ONE

  • No preview · Article · Apr 2012 · Journal of Hepatology
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    ABSTRACT: The involvement of bone marrow hematopoietic stem cells (BMHSC) mobilization during liver regeneration from hepatectomized patients is under debate. The main aim of this study was to investigate the role of BMHSC mobilization after hepatic resection in 33 patients with liver disease. Mobilization of CD34(+) BMHSC after 72 h of surgery was found in peripheral blood of some, but not all, of the hepatectomized patients. These CD34(+) cells co-expressed other stem cells markers. The patients without BMHSC mobilization showed high levels of circulating and liver tissue BMHSC (CD34(+) cells) previous to surgery. Therefore, two types of patients: "mobilizers" and "non-mobilizers" were distinguished based on the values of CD34(+) cells before and after surgery. Changes in cytokines involved in the hepatic regeneration (HGF and TGF-β), and in BMHSC mobilization process (SCF, SDF-1, IL-12, or MMP-2), were detected in both groups. In addition, a higher activation previous to surgery of the SDF-1/CXCR4 axis in liver tissue was observed in non mobilizers patients compared to mobilizer patients. BMHSC mobilization seems to be associated with variations in the levels of cytokines and proteolytic enzymes involved in hepatic regeneration and bone marrow matrix degradation. Hepatectomy may be an insufficient stimulus for BMSHC mobilization. The pre-hepatectomy higher levels CD34(+) cells in peripheral blood and liver, associated to the activation of hepatic SDF-1/CXCR4 axis, suggest a BMHSC mobilization process previous to surgery in non mobilizer patients.
    No preview · Article · Apr 2011 · Journal of Gastrointestinal Surgery
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    ABSTRACT: Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.
    No preview · Article · Aug 2008 · Chemico-Biological Interactions
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    ABSTRACT: Liver cell death is triggered by a number of insults arising from the external environment or from within the cell. These insults may engage cell surface receptors with death domaines leading to a proteolytic cascade involving initiator and executioner caspases and an apoptotic demise. Alternatively, the insults may profoundly disrupt mitochondrial function and result in loss of homeostasis accompanied by activation of hydrolases and a necrotic or lytic demise. The distinction between apoptotic and necrotic cell death has become blurred recently by the recognition that the same stimuli can induce either form of cell death as well as caspase independent apoptosis. Mitochondria play a key role in the shape of cell death; selective release of mediators amplifies the apoptosis program and profound loss of mitochondrial function leads to necrosis. Reactive oxygen metabolites and nitric oxide participate as intitiating factors and modulators. The extensive knowledge gained in recent years about the mechanisms of cell death will undoubtedly lead to new and exciting advances in the prevention and treatment of liver diseases. Important targets include death receptors, death signaling mechanisms, the mitochondrial permeability transition and approaches which selectively inhibit or activate cell death in parenchymal versus nonparenchymal cells.
    Full-text · Article · Aug 2007 · Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva

  • No preview · Article · Jul 2007 · Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva
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    ABSTRACT: Ovarian hormone depletion in ovariectomized experimental animals is a useful model with which to study the physiopathological consequences of menopause in women. It has been suggested that menopause is a risk factor for the induction of several cardiovascular disorders. In the present study we analyzed the effects of ovarian hormone depletion by ovariectomy (OVX) in a model of oxidative stress and cardiopathy induced by adriamycin (AD). To evaluate these effects, we measured parameters related to cardiac damage (creatinine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase) and oxidative stress (malondialdehyde, catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione, nitric oxide and carbonyl proteins) in cardiac tissue and erythrocytes. OVX was found to alter all markers of oxidative stress and cell damage in cardiac tissue. Similarly, the OVX-derived loss of ovarian hormones enhanced cardiac damage and oxidative stress induced by AD. Our results suggest that antioxidant status in cardiac tissue and erythrocytes is seriously compromised by OVX during the cardiomyopathy induced by AD in experimental animals. In conclusion, the absence of hormones caused by OVX or menopause may induce or accelerate pre-existing cardiovascular dysfunctions.
    No preview · Article · Mar 2006 · Gynecological Endocrinology