TY - JOUR
T1 - Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell–Derived Endothelial Cells
AU - Lee, Won Hee
AU - Ong, Sang Ging
AU - Zhou, Yang
AU - Tian, Lei
AU - Bae, Hye Ryeong
AU - Baker, Natalie
AU - Whitlatch, Adam
AU - Mohammadi, Leila
AU - Guo, Hongchao
AU - Nadeau, Kari C.
AU - Springer, Matthew L.
AU - Schick, Suzaynn F.
AU - Bhatnagar, Aruni
AU - Wu, Joseph C.
N1 - Publisher Copyright:
© 2019 American College of Cardiology Foundation
PY - 2019/6/4
Y1 - 2019/6/4
N2 - Background: Electronic cigarettes (e-cigarettes) have experienced a tremendous increase in use. Unlike cigarette smoking, the effects of e-cigarettes and their constituents on mediating vascular health remain understudied. However, given their increasing popularity, it is imperative to evaluate the health risks of e-cigarettes, including the effects of their ingredients, especially nicotine and flavorings. Objectives: The purpose of this study was to investigate the effects of flavored e-cigarette liquids (e-liquids) and serum isolated from e-cigarette users on endothelial health and endothelial cell–dependent macrophage activation. Methods: Human-induced pluripotent stem cell–derived endothelial cells (iPSC-ECs) and a high-throughput screening approach were used to assess endothelial integrity following exposure to 6 different e-liquids with varying nicotine concentrations and to serum from e-cigarette users. Results: The cytotoxicity of the e-liquids varied considerably, with the cinnamon-flavored product being most potent and leading to significantly decreased cell viability, increased reactive oxygen species (ROS) levels, caspase 3/7 activity, and low-density lipoprotein uptake, activation of oxidative stress-related pathway, and impaired tube formation and migration, confirming endothelial dysfunction. Upon exposure of ECs to e-liquid, conditioned media induced macrophage polarization into a pro-inflammatory state, eliciting the production of interleukin-1β and -6, leading to increased ROS. After exposure of human iPSC-ECs to serum of e-cigarette users, increased ROS linked to endothelial dysfunction was observed, as indicated by impaired pro-angiogenic properties. There was also an observed increase in inflammatory cytokine expression in the serum of e-cigarette users. Conclusions: Acute exposure to flavored e-liquids or e-cigarette use exacerbates endothelial dysfunction, which often precedes cardiovascular diseases.
AB - Background: Electronic cigarettes (e-cigarettes) have experienced a tremendous increase in use. Unlike cigarette smoking, the effects of e-cigarettes and their constituents on mediating vascular health remain understudied. However, given their increasing popularity, it is imperative to evaluate the health risks of e-cigarettes, including the effects of their ingredients, especially nicotine and flavorings. Objectives: The purpose of this study was to investigate the effects of flavored e-cigarette liquids (e-liquids) and serum isolated from e-cigarette users on endothelial health and endothelial cell–dependent macrophage activation. Methods: Human-induced pluripotent stem cell–derived endothelial cells (iPSC-ECs) and a high-throughput screening approach were used to assess endothelial integrity following exposure to 6 different e-liquids with varying nicotine concentrations and to serum from e-cigarette users. Results: The cytotoxicity of the e-liquids varied considerably, with the cinnamon-flavored product being most potent and leading to significantly decreased cell viability, increased reactive oxygen species (ROS) levels, caspase 3/7 activity, and low-density lipoprotein uptake, activation of oxidative stress-related pathway, and impaired tube formation and migration, confirming endothelial dysfunction. Upon exposure of ECs to e-liquid, conditioned media induced macrophage polarization into a pro-inflammatory state, eliciting the production of interleukin-1β and -6, leading to increased ROS. After exposure of human iPSC-ECs to serum of e-cigarette users, increased ROS linked to endothelial dysfunction was observed, as indicated by impaired pro-angiogenic properties. There was also an observed increase in inflammatory cytokine expression in the serum of e-cigarette users. Conclusions: Acute exposure to flavored e-liquids or e-cigarette use exacerbates endothelial dysfunction, which often precedes cardiovascular diseases.
KW - e-cigarette aerosol
KW - e-liquid flavoring
KW - endothelial dysfunction
KW - iPSC-ECs
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U2 - 10.1016/j.jacc.2019.03.476
DO - 10.1016/j.jacc.2019.03.476
M3 - Article
C2 - 31146818
AN - SCOPUS:85065740078
SN - 0735-1097
VL - 73
SP - 2722
EP - 2737
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 21
ER -