Author + information
- Received June 20, 2018
- Revision received February 28, 2019
- Accepted March 3, 2019
- Published online May 27, 2019.
- Won Hee Lee, PhDa,b,∗∗∗ (, )
- Sang-Ging Ong, PhDa,c,d,∗,
- Yang Zhou, MSa,
- Lei Tian, PhDa,
- Hye Ryeong Bae, BSa,
- Natalie Baker, BSa,
- Adam Whitlatch, BSe,
- Leila Mohammadi, MD, PhDf,
- Hongchao Guo, PhDa,g,
- Kari C. Nadeau, MD, PhDh,
- Matthew L. Springer, PhDe,f,
- Suzaynn F. Schick, PhDi,
- Aruni Bhatnagar, PhDj and
- Joseph C. Wu, MD, PhDa,g,∗ (, )@StanfordCVI
- aStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California
- bDepartment of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
- cDepartment of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois
- dDivision of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois
- eDepartment of Medicine, Division of Cardiology, University of California, San Francisco, California
- fDepartment of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California
- gDepartment of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California
- hSean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California
- iSchool of Medicine, Division of Occupational and Environmental Medicine, University of California, San Francisco, California
- jDivision of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, Kentucky
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.
↵∗ Drs. Lee and Ong contributed equally to this work.
This work was supported by the American Heart Association (AHA) Scientist Development Grant 16SDG27560003 (to Dr. Lee), a Pilot Award from the Stanford Diabetes Research Center from a grant sponsored by the National Institutes of Health (NIH) P30DK116074 (to Dr. Lee), NIH R00 HL130416 (to Dr. Ong), NIH R01 HL141371 (to Dr. Wu), University of California Tobacco Related Disease Research Program 27IR-0012 (to Dr. Wu), AHA 17MERIT33610009 (to Dr. Wu), NIH P50-CA-180890-01 and the U.S. Food and Drug Administration Center for Tobacco Products (to Dr. Schick), University of California Tobacco Related Disease Research Program 24RT-0039 (to Dr. Schick), NIH R01 HL120062 and the U.S. Food and Drug Administration Center for Tobacco Products (to Dr. Springer), and NIH U54 HL120163 (to Dr. Bhatnagar). Dr. Springer’s wife is on advisory boards for Bayer, ADC Therapeutics, and Seattle Genetics. Dr. Wu is a co-founder of Khloris Biosciences but has no competing interests, as the work presented here is completely independent. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received June 20, 2018.
- Revision received February 28, 2019.
- Accepted March 3, 2019.
- 2019 American College of Cardiology Foundation
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