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VASCULAR BIOLOGY

Cytotoxicity of water-soluble fullerene in vascular endothelial cells

Department of Epidemiology, Research Institute, National Cardiovascular Center, Suita, Osaka, Japan

Submitted 27 September 2005 ; accepted in final form 4 January 2006

Nanoscale materials are presently under development for diagnostic (nanomedicine) and electronic purposes. In contrast to the potential benefits of nanotechnology, the effects of nanomaterials on human health are poorly understood. Nanomaterials are known to translocate into the circulation and could thus directly affect vascular endothelial cells (ECs), causing vascular injury that might be responsible for the development of atherosclerosis. To explore the direct effects of nanomaterials on endothelial toxicity, human umbilical vein ECs were treated with 1–100 µg/ml hydroxyl fullerene [C₆₀(OH)₂₄; mean diameter, 7.1 ± 2.4 nm] for 24 h. C₆₀(OH)₂₄ induced cytotoxic morphological changes such as cytosolic vacuole formation and decreased cell density in a dose-dependent manner. Lactate dehydrogenase assay revealed that a maximal dose of C₆₀(OH)₂₄ (100 µg/ml) induced cytotoxic injury. Proliferation assay also showed that a maximal dose of C₆₀(OH)₂₄ inhibited EC growth. C₆₀(OH)₂₄ did not seem to induce apoptosis but caused the accumulation of polyubiquitinated proteins and facilitated autophagic cell death. Formation of autophagosomes was confirmed on the basis of Western blot analysis using a specific marker, light chain 3 antibody, and electron microscopy. Chronic treatment with low-dose C₆₀(OH)₂₄ (10 µg/ml for 8 days) inhibited cell attachment and delayed EC growth. In the present study, we have examined, for the first time, the toxicity of water-soluble fullerenes to ECs. Although fullerenes changed morphology in a dose-dependent manner, only maximal doses of fullerenes caused cytotoxic injury and/or death and inhibited cell growth. EC death seemed to be caused by activation of ubiquitin-autophagy cell death pathways. Although exposure to nanomaterials appears to represent a risk for cardiovascular disorders, further in vivo validations are necessary.

nanomaterials; ubiquitin proteasome; autophagy; atherosclerosis

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