Atherogenic Mechanisms of Electronic Nicotine Delivery Systems

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Nicotine is an abundant toxicant in various tobacco products including cigarette smoke, smokeless tobacco, cigars, cigarillos, and hookah. The use of tobacco products increase the risk for atherosclerosis. Although usage of conventional cigarette has steadily declined over the last three decades, usage of new and emerging tobacco products and electronic nicotine delivery systems (ENDS) such as electronic cigarettes (e-cig), e-hookah, and e-cigars has increased exponentially. ENDS aerosolize a solution known as an “e-liquid” (typically a combination of propylene glycol, PG, and vegetable glycerol, VG) that contains a small percentage of nicotine. Although several combustion products and toxins such as CO and tobacco-specific nitrosamines are non-detectable in ENDS, carbonyls including short-chain toxic aldehydes (acrolein, formaldehyde, acetaldehyde, etc.) have been detected in e-cig-derived aerosols up to levels found in tobacco smoke. Our preliminary data suggest that exposure to e-cig or its components, such as acrolein and nicotine (oral exposure) induce macrophage activation (cytokine formation, MMP activation, and apoptosis) and exacerbate atherosclerosis. Conversely, quenching of endogenous aldehydes by feeding with the endogenous dipeptide - carnosine (β-ala-his) or overexpressing carnosine synthase in macrophages prevents atherosclerosis. Our preliminary studies also show that chronic exposure to e-cig, nicotine, and acrolein increase the expression of micro RNA-21 (miR-21) in the aortae of atherogenic mice; and acrolein and nicotine induce miR-21 in macrophages in culture, presumable as an adaptive response to macrophage activation. Based on these observations we hypothesize that miR-21 decreases ENDS-induced atherogenesis by preventing macrophage activation by ENDS-derived aldehydes and nicotine. To test this hypothesis, we will 1) Examine the effect of e-cig on atherogenesis. In LDL receptor- null mice exposed to filtered air, varying proportions of propylene glycol (PG):vegetable glycerin (VG), PG:VG + nicotine, and JUUL-specific e-liquids, we will quantify the time-, dose-, and sex- dependent changes in atherosclerotic lesion formation. We will examine how ENDS and their components affect the plaque composition, the nature, and the stability; 2) Delineate the atherogenic contribution of ENDS-derived aldehydes. We will examine whether quenching of e- liquid and ENDS-derived aldehydes by oral feeding with carnosine or macrophage-specific overexpression of carnosine synthase prevents macrophage activation and atherogenesis and how are these processes regulated by miR-21; 3) Elucidate the atherogenicity of ENDSderived nicotine. We will probe how ENDS activate macrophage α7nAChR, and how macrophage-specific deficiency of α7nAChR affects ENDS-induced macrophage activation and atherogenesis. We will also examine how miR-21 regulates these processes. Overall, the proposed studies will establish novel animal models of ENDS-induced atherosclerosis, and delineate the underling chemical, cellular, and molecular mechanisms of toxicity.