Abstract 13745: Electronic Cigarette-Derived Aerosols Induce Endothelial Dysfunction: Role of Aldehydes and Transient Receptor Potential Ankyrin-1 in Mice

Abstract

Introduction: Electronic cigarettes (e-cigs) threaten to reverse the decline in rates of nicotine dependence and smoking. While some believe that e-cigarettes are less harmful than combustible cigarettes, e-cig use is associated with respiratory symptoms (cough, wheeze) and endothelial dysfunction (ED) indicating a potential to increase the risk of cardiovascular disease (CVD) with chronic use. ED is sine qua non of multiple CVD, yet the mechanism of e-cig-induced ED is unknown. Hypothesis: E-cigs generate levels of irritants that activate the Transient Receptor Potential Ankyrin-1 (TRPA1) to trigger nocifensive reflexes and induce ED in mice. Methods: Wild type (WT) and TRPA1-null C57BL/6J male and female mice were exposed to: filtered air (control), aerosols of JUUL e-cig liquid, e-cig solvents without nicotine (propylene glycol:glycerin, PG:G), or irritant gases alone (acrolein, formaldehyde). Urinary levels of nicotine and aldehyde metabolites were measured by UPLC-MS/MS. During acute exposures, respiratory irritant responses were monitored by radiotelemetry. Following short-term exposure (4d), aortic endothelial function, blood/plasma markers of organ toxicity, and platelet activation were measured. Results: Exposure of WT mice to e-cig aerosols increased urine levels of the acrolein, but not formaldehyde, metabolite (3HPMA), to that of exposures to 1 ppm acrolein alone. In WT mice, exposure to either PG:G (30:70), formaldehyde (5 ppm), or acrolein (1 ppm) induced respiratory braking. In female WT mice (n=5-18), exposure to PG:G (-61.8±4.2 % ACh relaxation) and formaldehyde (–56.3 ± 4.5 %) but not acrolein (-80.0±3.2 %) induced ED vs control group (-77.8±1.5 %). In female TRPA1-null mice (n=5-14), neither PG:G (-77.6±3.6 %), formaldehyde (-85.9±7.8 %) nor acrolein (-86.6±2.8 %) exposure induced ED vs control (-81.3±5.4 %). Acrolein exposure enhanced aortic sensitivity to an NO donor similarly in female WT and TRPA1-null mice. Conclusions: Formaldehyde and acrolein generated from the PG:G in e-cigs provoked pulmonary irritant reflexes, and formaldehyde exposure alone induced ED in female mice. Irritant aldehydes in e-cig-derived aerosols activate the TRPA1 receptor to promote ED that could increase CVD risk.