title: Amorphous silica nanoparticles aggregate human platelets: potential implications for vascular homeostasis.
abstract: BACKGROUND
  Amorphous silica nanoparticles (SiNP) can be used in medical technologies and other industries leading to human exposure. However, an increased number of studies indicate that this exposure may result in cardiovascular inflammation and damage. A high ratio of nitric oxide to peroxynitrite concentrations ([NO]/[ONOO(-)]) is crucial for cardiovascular homeostasis and platelet hemostasis. Therefore, we studied the influence of SiNP on the platelet [NO]/[ONOO(-)] balance and platelet aggregation.
  
  
  METHODS
  Nanoparticle-platelet interaction was examined using transmission electron microscopy. Electrochemical nanosensors were used to measure the levels of NO and ONOO(-) released by platelets upon nanoparticle stimulation. Platelet aggregation was studied using light aggregometry, flow cytometry, and phase contrast microscopy.
  
  
  RESULTS
  Amorphous SiNP induced NO release from platelets followed by a massive stimulation of ONOO(-) leading to an unfavorably low [NO]/[ONOO(-)] ratio. In addition, SiNP induced an upregulation of selectin P expression and glycoprotein IIb/IIIa activation on the platelet surface membrane, and led to platelet aggregation via adenosine diphosphate and matrix metalloproteinase 2-dependent mechanisms. Importantly, all the effects on platelet aggregation were inversely proportional to nanoparticle size.
  
  
  CONCLUSIONS
  The exposure of platelets to amorphous SiNP induces a critically low [NO]/[ONOO(-)] ratio leading to platelet aggregation. These findings provide new insights into the pharmacological profile of SiNP in platelets.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences, Panoz Institute, Trinity College Dublin, Ireland.
authors.forename: J Jose
authors.initials: JJ
authors.lastname: Corbalan
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
authors.forename: Adam
authors.initials: A
authors.lastname: Jacoby
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Malinski
authors.forename: Marek W
authors.initials: MW
authors.lastname: Radomski
mesh_terms: D000704:Analysis of Variance; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D009569:Nitric Oxide / Q000097:blood; D010316:Particle Size; D030421:Peroxynitrous Acid / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D012822:Silicon Dioxide / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D012822:Silicon Dioxide