Effects of chronic treatment with sodium tetrachloroaurate(III) in mice and membrane models

Suwalsky, Mario; Zambenedetti, Pamela; Carpenè, Emilio; IbnLkayat, Meryem; Wittkowski, W.; Messori, Luigi; Zatta, Paolo

doi:10.1016/j.jinorgbio.2004.09.015

Cited by 10 publications

(3 citation statements)

References 26 publications

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“…It is worth to emphasize that the doses of Au(III) administered during in vivo part of our study (1-10 mg/kg) correspond to the concentration range of approximately 40-400 μM (calculations based on the weight of animals used and predicted amount of circulating blood). These Au(III) concentrations have been previously found to completely block platelet secretion without producing disturbances in erythrocytes' membranes in whole human blood (Misztal et al, 2018), reported by other authors in red blood cells suspended in artificial media (Suwalsky et al, 2004). It is worth to emphasize that in this experimental model, the presence of erythrocytes within thrombi is expected (Ciciliano et al, 2015).…”

Section: Engagement Of Aqps In Platelet Procoagulant Responsesupporting

confidence: 66%

HAuCl4, Putative General Aquaporins Blocker, Reduces Platelet Spreading, Filopodia Formation, Procoagulant Response, and Thrombus Formation Under Flow

et al. 2020

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Background: Recent studies indicate that aquaporin (AQP) water channels have a regulatory function in human platelet secretion and in procoagulant response of murine platelets. However, the engagement of AQPs in morphological changes, procoagulant response, and thrombus formation in human blood has never been investigated. Methods: Confocal microscopy was used to study platelet spreading, filopodia formation, ballooning, and thrombus formation under flow. Flow cytometry was utilized to assess platelet phosphatidylserine (PS) exposure and microparticles shedding. Kinetics of clot formation in vitro was evaluated by thromboelastometry. Mouse model of ferric chloride (III) (FeCl 3)-induced thrombosis was used to investigate thrombus formation in vivo. Results: We found that chloroauric(III) acid (HAuCl 4), a classical AQP inhibitor (10-100 μM), reduced spreading of human platelets on collagen-coated surfaces and inhibited filopodia formation in a fluid phase. Under flow conditions, HAuCl 4 (100 μM) attenuated thrombi growth on collagen, platelet secretion, and PS exposure. Thrombus formation was restored by the addition of exogenous adenosine diphosphate (ADP). Collagen-evoked platelet procoagulant response (evaluated as PS exposure, shedding of microparticles, plateletdependent thrombin generation, and membrane ballooning) was distinctly reduced by HAuCl 4 (25-200 μM), as well as the dynamics of clot formation. In mouse model of thrombosis, reduction of surface of PS-positive cells within thrombus was observed in the presence of HAuCl 4 (1-10 mg/kg). Conclusion: These results suggest that in human platelets AQPs are crucial for agonistevoked morphological changes, thrombus formation under flow, and in development of procoagulant response. Antithrombotic effect in vivo suggests that nontoxic inhibitors of AQPs may be considered as potential candidates for a novel class of antiplatelet drugs.

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Section: Engagement Of Aqps In Platelet Procoagulant Responsesupporting

confidence: 66%

HAuCl4, Putative General Aquaporins Blocker, Reduces Platelet Spreading, Filopodia Formation, Procoagulant Response, and Thrombus Formation Under Flow

et al. 2020

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“…Au(III) compounds are much less toxic than commonly used 0.3 M mercury chloride. Experiments with NaAuCl 4 reveal its relatively low toxicity to mice (Suwalsky et al, 2004). However in the same study it was also suggested that NaAuCl 4 (at 0.1-10 mM concentrations) may affect morphology (shape) of red blood cells suspended in an artificial medium.…”

Section: Discussionmentioning

confidence: 88%

Aquaporins in human platelets: intracellular localization and possible role in granule and lysosome secretion

Misztal¹,

Rusak²,

Brańska-Januszewska³

et al. 2018

Acta Biochim Pol

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This study was undertaken to establish the presence and the role of aquaporins (AQPs) in human platelets. Immunodetection with polyclonal antibodies and fluorescent microscopy suggest the presence of AQP isoforms – 0–7 and 9–12 – localized (in resting platelets) in the plasma membrane and in the dense and alpha granules. In thrombin- or monensin-treated platelets, the granules’ AQPs become visible in the whole cell body, indicating the granules’ swelling. In our studies on the role of AQPs in platelet responses we used tetrachloroauric acid (HAuCl4), a classical water channel blocker. We found that 10–100 µM of Au(III) inhibited the hypotonicity-, monensin (simulating the action of Na+/H+ exchanger)-, and collagen-evoked platelet swelling and reduced tritiated water uptake by platelets treated by collagen or monensin, indicating its ability to block water channels in these cells. HAuCl4, at the concentrations reducing water influx, did not induce cell lysis, alter the plasma membrane shape or the –SH group content. The inhibitor also failed to affect Na+ and Cl--related osmotic gradient formation and protein kinase D2 phosphorylation. In platelets activated by threshold concentrations of collagen, the thrombin receptor activating peptide, ADP, calcium ionophore A23187, phorbol ester and arachidonic acid, HAuCl4 (100 µM) completely inhibited secretion of ATP from dense granules but failed to reduce platelet aggregation. In collagen-stimulated platelets, HAuCl4 (10–100 µM) reduced secretion from dense and alpha granules, as well as lysosomes, in a dose-dependent manner. We conclude that human platelets possess numerous AQPs subtypes localized in the plasma and granule membranes. AQP-mediated water fluxes may be crucial for platelet volume regulation as well as secretion from dense and alpha granules and lysosomes.

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“…In an attempt to further elucidate the effect of auranofin on cell membranes, its influence on the morphology of intact human erythrocytes was examined by scanning electron microscopy (SEM). These systems and techniques have been previously used to determine the membrane-perturbing effects of other Au(I) and Au(III) compounds 12,13,14 . Additional experiments were performed in human neuroblastoma cells SH-SY5Y in order to test the toxicity after treatments with auranofin.…”

Section: Introductionmentioning

confidence: 99%

Structural Effects of the Au(i) Drug Auranofin on Cell Membranes and Molecular Models

Suwalsky¹,

González²,

Villena³

et al. 2013

J. Chil. Chem. Soc.

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Auranofin is a gold compound that is widely used for the treatment of rheumatoid arthritis. It is a monomeric linear complex with triethylphosphine and thiolate moieties bounded to an Au(I) center. Gold compounds are well known for their neurological and nephrotoxic implications. However, haematological toxicity is one of the most serious toxic and less studied effects. The lack of information on these aspects of auranofin prompted us to study the structural effects induced on cell membranes, particularly that of human erythrocytes. Auranofin was incubated with intact erythrocytes and molecular models of the erythrocyte membrane. The latter consisted of multibilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipids classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. This report presents evidence in order that auranofin interacts with red cell membranes as follows: a) in scanning electron microscopy studies on human erythrocytes it was observed that auranofin induced shape changes; b) X-ray diffraction studies showed that auranofin induced increasing structural perturbation to DMPC and to a lower extent to DMPE bilayers. Additional experiments were performed in human neuroblastoma cells SH-SY5Y. A statistically significant decrease of cell viability was observed.

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Effects of chronic treatment with sodium tetrachloroaurate(III) in mice and membrane models

Cited by 10 publications

References 26 publications

HAuCl4, Putative General Aquaporins Blocker, Reduces Platelet Spreading, Filopodia Formation, Procoagulant Response, and Thrombus Formation Under Flow

HAuCl4, Putative General Aquaporins Blocker, Reduces Platelet Spreading, Filopodia Formation, Procoagulant Response, and Thrombus Formation Under Flow

Aquaporins in human platelets: intracellular localization and possible role in granule and lysosome secretion

Structural Effects of the Au(i) Drug Auranofin on Cell Membranes and Molecular Models

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