Conventional and electronic cigarettes dysregulate the expression of iron transporters and detoxifying enzymes at the brain vascular endothelium: In vivo evidence of a gender-specific cellular response to chronic cigarette smoke exposure

Neurosci Lett. 2018 Aug 24;682:1-9. doi: 10.1016/j.neulet.2018.05.045. Epub 2018 Jun 4.


It is well established that tobacco smoking is associated with vascular endothelial dysfunction in a causative and dose dependent manner primarily related to the tobacco smoke (TS) content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS) -driven inflammation. Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes (e-Cigs) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to vascular endothelial dysfunctions. Herein, we provide direct evidence that similarly to TS, e-Cig promotes mitochondrial depolarization in primary brain vascular endothelial cells as well as the vascular endothelial cell line bEnd3. In addition, both TS and e-Cig exposure upregulated the transmembrane iron exporter Slc40a1 (crucial to maintain cellular iron and redox homeostasis) and that of porphyrin importer Abcb6 (linked to accelerated atherosclerosis). We then investigated in vivo whether gender plays a role in how chronic TS affect vascular endothelial functions. Our results clearly show chronic TS exposure differentially impacts the expression levels of Phase-II enzymes as well as the iron transporters previously investigated in vitro. Although the physiological implications of the gender-specific differential responses to TS are not fully clear, they do demonstrate that gender is a risk factor that needs to be investigated when assessing the potential impact of chronic smoking and perhaps e-Cig vaping.

Keywords: Abc transporter; Blood brain barrier; Ferroportin1; Gender; MitoChip; Nrf2; Redox.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain / blood supply
  • Brain / drug effects
  • Brain / metabolism
  • Cation Transport Proteins / biosynthesis*
  • Cation Transport Proteins / genetics
  • Cell Line
  • Cigarette Smoking / adverse effects
  • Cigarette Smoking / metabolism*
  • Electronic Nicotine Delivery Systems* / methods
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Female
  • Gene Expression
  • Inhalation Exposure / adverse effects
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Mice
  • Mice, Inbred C57BL
  • Sex Characteristics*


  • Cation Transport Proteins
  • metal transporting protein 1