Won Hee Lee1, Sang-Ging Ong2, Yang Zhou3, Lei Tian3, Hye Ryeong Bae3, Natalie Baker3, Adam Whitlatch4, Leila Mohammadi5, Hongchao Guo6, Kari C Nadeau7, Matthew L Springer8, Suzaynn F Schick9, Aruni Bhatnagar10, Joseph C Wu11. 1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California; Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona. Electronic address: whlee@email.arizona.edu. 2. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California; Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois; Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois. 3. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California. 4. Department of Medicine, Division of Cardiology, University of California, San Francisco, California. 5. Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California. 6. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California; Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California. 7. Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California. 8. Department of Medicine, Division of Cardiology, University of California, San Francisco, California; Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California. 9. School of Medicine, Division of Occupational and Environmental Medicine, University of California, San Francisco, California. 10. Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, Kentucky. 11. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California; Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California. Electronic address: joewu@stanford.edu.
Abstract
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.
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 humaniPSC-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.
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