The effects of subacute inhaled multi-walled carbon nanotube exposure on signaling pathways associated with cholesterol transport and inflammatory markers in the vasculature of wild-type mice

Toxicol Lett. 2018 Oct 15;296:48-62. doi: 10.1016/j.toxlet.2018.08.004. Epub 2018 Aug 3.


Exposure to multi-walled carbon nanotubes (MWCNTs) has been associated with detrimental cardiovascular outcomes; however, underlying mechanisms have not yet been fully elucidated. Thus, we investigated alterations in proatherogenic and proinflammatory signaling pathways in C57Bl6/ mice exposed to MWCNTs (1 mg/m3) or filtered air (FA-Controls), via inhalation, for 6 h/day, 14d. Expression of mediators of cholesterol transport, namely the lectin-like oxidized low-density lipoprotein receptor (LOX)-1 and ATP-binding cassette transporter (ABCA)-1, inflammatory markers tumor necrosis factor (TNF)-α and interleukin (IL)-1β/IL-6, nuclear-factor kappa-light-chain-enhancer of activated B cells (NF-κB), intracellular/vascular adhesion molecule(s) (VCAM-1, ICAM-1), and miRNAs (miR-221/-21/-1), associated with cardiovascular disease (CVD), were analyzed in cardiac tissue and coronary vasculature. Cardiac fibrotic deposition, matrix-metalloproteinases (MMP)-2/9, and reactive oxygen species (ROS) were also assessed. MWCNT-exposure resulted in increased coronary ROS production with concurrent increases in expression of LOX-1, VCAM-1, TNF-α, and MMP-2/9 activity; while ABCA-1 expression was downregulated, compared to FA-Controls. Additionally, trends in fibrotic deposition and induction of cardiac TNF-α, MMP-9, IκB Kinase (IKK)-α/β, and miR-221 mRNA expression were observed. Analysis using inhibitors for nitric oxide synthase or NADPH oxidase resulted in attenuated coronary ROS production. These findings suggest that subacute inhalation MWCNT-exposure alters expression of cholesterol transporter/receptors, and induces signaling pathways associated with inflammation, oxidative stress, and CVD in wild-type mice.

Keywords: Coronary arteries; LOX-1; MWCNT; ROS; miRNA.

MeSH terms

  • ATP Binding Cassette Transporter 1 / biosynthesis
  • Administration, Inhalation
  • Animals
  • Cardiovascular Diseases / metabolism
  • Cell Adhesion Molecules / biosynthesis
  • Cholesterol / metabolism*
  • Collagen / metabolism
  • Inflammation Mediators / metabolism*
  • Interleukins / biosynthesis
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Nanotubes, Carbon / toxicity*
  • Reactive Oxygen Species
  • Scavenger Receptors, Class E / biosynthesis
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • ABCA1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • Cell Adhesion Molecules
  • Inflammation Mediators
  • Interleukins
  • NF-kappa B
  • Nanotubes, Carbon
  • Olr1 protein, mouse
  • Reactive Oxygen Species
  • Scavenger Receptors, Class E
  • Tumor Necrosis Factor-alpha
  • Collagen
  • Cholesterol
  • Matrix Metalloproteinases