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Amorphous SiO2 nanoparticles promote cardiac dysfunction via the opening of the mitochondrial permeability transition pore in rat heart and human cardiomyocytes
- Source :
- Particle and Fibre Toxicology, Particle and Fibre Toxicology, Vol 17, Iss 1, Pp 1-16 (2020)
- Publication Year :
- 2020
- Publisher :
- BioMed Central, 2020.
-
Abstract
- Background Silica nanoparticles (nanoSiO2) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO2 has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO2. Results The cumulative administration of nanoSiO2 reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 μg/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO2 was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (ΔΨm). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO2 and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO2 exposure, suggesting that nanoSiO2 induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO2, enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO2-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO2 in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 μg/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO2, reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO2 affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. Conclusion The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO2 exposure.
- Subjects :
- Male
Health, Toxicology and Mutagenesis
02 engineering and technology
Mitochondrion
Pharmacology
Toxicology
medicine.disease_cause
chemistry.chemical_compound
Adenosine Triphosphate
Myocyte
Myocytes, Cardiac
Calcium overload
Cells, Cultured
Cardioprotection
Membrane Potential, Mitochondrial
0303 health sciences
Chemistry
MPTP
Heart
General Medicine
021001 nanoscience & nanotechnology
Silicon Dioxide
Silica nanoparticles
Mitochondria
0210 nano-technology
Cell Survival
Surface Properties
lcsh:Industrial hygiene. Industrial welfare
Oxidative phosphorylation
Permeability transition
03 medical and health sciences
lcsh:RA1190-1270
medicine
Animals
Humans
Particle Size
Rats, Wistar
lcsh:Toxicology. Poisons
030304 developmental biology
Dose-Response Relationship, Drug
Mitochondrial Permeability Transition Pore
Research
Myocardium
Cardiotoxicity
Rats
Oxidative Stress
Mitochondrial permeability transition pore
Apoptosis
Nanoparticles
Reactive Oxygen Species
lcsh:HD7260-7780.8
Oxidative stress
Subjects
Details
- Language :
- English
- ISSN :
- 17438977
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Particle and Fibre Toxicology
- Accession number :
- edsair.doi.dedup.....54d59fdf5a0f71c39e062b8ef0ff8655