Impairment of endothelial function by cigarette smoke and e-cigarette aerosol requires RAGE

Introduction: Although e-cigarette is known to cause detrimental physiological alterations in the cardiovascular system, the molecular mechanism of e-cigarette-induced vascular impairment is relatively unexplored. We investigated whether the inhibition of RAGE prevents impairment of vasomotor function from acute and chronic e-cigarette exposure. Hypothesis: RAGE is required to cause e-cigarette-induced impairment of endothelial vasodilation. Methods: In both exposure settings, anaesthetized rats (n=8/group) were exposed to aerosols from flavorless tank-style e-cigarettes with and without freebase nicotine (12 mg/mL) or air. For acute exposure, exposure was done in a singles session of 10 cycles of pulsatile 5s exposure over 5 minutes using a Gram REsearch analytical vaping machine drawing 55ml. All rats received RAGEi or DMSO i.p. 1h pre-exposure. FMD was measured pre-exposure and 10 minutes after the end of the exposure. For sub-acute exposure, the exposure consisted of a single session of 120 cycles of pulsatile 5s exposure over 1h/day for 2 weeks. All the rats received RAGEi or DMSO i.p. 1h pre-exposure daily during acclimation and exposure (total of 3 weeks). Echocardiography was conducted one day before the end of the experiment. FMD was measured before and after the exposure on the last day of the experiment. Results: Exposure to e-cigarette aerosol with and without nicotine impaired FMD in vehicle groups in both acute and subacute exposures with no change in air control. As expected, the positive control of cigarette exposure impaired FMD in the vehicle group in acute settings. However, FPS-ZM1 prevented the FMD impairment in e-cigarette aerosol exposures and cigarette exposures in both acute and subacute exposures with no changes in air control. Conclusions: RAGE plays a role in mediating e-cigarette-induced acute and sub-acute impairment of endothelial vasodilatory function.Brachial Analyzer (Medical Imaging Applications, Coralville, IA) and VevoLab software are required to open the data files. See Methods above for details. Funding provided by: National Heart, Lung, and Blood InstituteCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000050Award Number: Funding provided by: U.S. Food and Drug AdministrationCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000038Award Number: Funding provided by: Elfenworks Foundation*Crossref Funder Registry ID: Award Number:For femoral artery diameter data, raw ultrasound data were collected by a Vevo 3100LT micro-ultrasound system (VisualSonics Inc., Toronto, Canada). Ultrasound images were processed and femoral artery diameter was measured by an automated system (Brachial Analyzer, Medical Imaging Applications, Coralville, IA). For cardiac function data, raw echocardiograms was collected by a Vevo 3100LT micro-ultrasound system (VisualSonics Inc., Toronto, Canada) and echocardiographic parameters were measured by a VevoLab software (VisualSonics Inc., Toronto, Canada)