title: Silica nanoparticles induce cardiotoxicity interfering with energetic status and Ca2+handling in adult rat cardiomyocytes.
abstract: Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2cell membrane association and internalization were analyzed. SiO2showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+handling, which showed impaired contractility and intracellular Ca2+transient amplitude during β-adrenergic stimulation in SiO2treatment. The time to 50% Ca2+decay increased 39%, and the Ca2+spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2generation were also observed. These data indicate that SiO2increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+release, and reduced cell shortening. This mechanism of SiO2cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHYSilica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+handling.
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.|Centro de Investigación Biomédica, Hospital Zambrano-Hellion, Tecnológico de Monterrey, San Pedro Garza-García, México.
authors.forename: Carlos Enrique
authors.identifier: http://orcid.org/0000-0002-5001-0093
authors.initials: CE
authors.lastname: Guerrero-Beltrán
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.
authors.forename: Judith
authors.initials: J
authors.lastname: Bernal-Ramírez
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.|Namur Nanosafety Centre, Namur Research Institute for Life Sciences, Research Centre for the Physics of Matter and Radiation, University of Namur, Namur, Belgium.
authors.forename: Omar
authors.initials: O
authors.lastname: Lozano
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.
authors.forename: Yuriana
authors.initials: Y
authors.lastname: Oropeza-Almazán
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.
authors.forename: Elena Cristina
authors.initials: EC
authors.lastname: Castillo
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.
authors.forename: Jesús Roberto
authors.initials: JR
authors.lastname: Garza
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.|Centro de Investigación Biomédica, Hospital Zambrano-Hellion, Tecnológico de Monterrey, San Pedro Garza-García, México.
authors.forename: Noemí
authors.initials: N
authors.lastname: García
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vela
authors.affiliation: Centro de Investigación en Materiales Avanzados S.C. Unidad Monterrey, Apodaca Nuevo León, México.
authors.forename: Alejandra
authors.identifier: http://orcid.org/0000-0001-7794-135X
authors.initials: A
authors.lastname: García-García
authors.affiliation: Department of Physics and Astronomy, The University of Texas at San Antonio, San Antonio, Texas.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ortega
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.|Centro de Investigación Biomédica, Hospital Zambrano-Hellion, Tecnológico de Monterrey, San Pedro Garza-García, México.|Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas; and.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
authors.affiliation: Laboratorio de Nanotecnología Ambiental, Centro del Agua, Tecnológico de Monterrey, Monterrey, México.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ornelas-Soto
authors.affiliation: Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México; gdejesus@itesm.mx.|Centro de Investigación Biomédica, Hospital Zambrano-Hellion, Tecnológico de Monterrey, San Pedro Garza-García, México.
authors.forename: Gerardo
authors.identifier: http://orcid.org/0000-0003-4731-3293
authors.initials: G
authors.lastname: García-Rivas
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D066126:Cardiotoxicity / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D053758:Nanoparticles / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D012822:Silicon Dioxide; D000255:Adenosine Triphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005978:Glutathione; D002118:Calcium
keywords: Ca2+; cardiomyocyte; nanoparticle; silicon dioxide; toxicity