Atherogenic Mechanisms of Electronic Nicotine Delivery Systems

尼古丁是包括香烟烟雾在内的各种烟草制品中的大量有毒物质， 无烟烟草、雪茄、小雪茄和水烟。烟草制品的使用增加了风险 治疗动脉粥样硬化尽管传统香烟的使用在过去几年中稳步下降， 三十年来，新的和新兴的烟草产品的使用和电子尼古丁输送 电子烟（e-cig）、电子水烟（e-hookah）和电子雪茄（e-cigars）等电子烟系统（ENDS）的使用量增加。 呈指数增长ENDS使被称为“电子液体”的溶液（通常是以下物质的组合）雾化： 丙二醇，PG和植物甘油，VG），其含有小百分比的尼古丁。 虽然一些燃烧产物和毒素，如CO和烟草特有的亚硝胺 在ENDS中是检测不到的，羰基包括短链有毒醛（丙烯醛， 甲醛、乙醛等）在电子烟产生的气溶胶中检测到的含量 在烟草烟雾中发现。我们的初步数据表明，接触电子烟或其成分， 例如丙烯醛和尼古丁（口服暴露）诱导巨噬细胞活化（细胞因子形成， MMP激活和细胞凋亡）并加剧动脉粥样硬化。相反， 内源性醛通过用内源性二肽-肌肽（β-ala-his）喂养或 巨噬细胞中肌肽合酶的过度表达可预防动脉粥样硬化。我们的初步 研究还表明，长期接触电子烟、尼古丁和丙烯醛会增加 在致动脉粥样硬化小鼠的动脉中的microRNA-21（miR-21）的表达;丙烯醛和尼古丁诱导 培养物中巨噬细胞中的miR-21，推测为对巨噬细胞的适应性反应 activation.基于这些观察结果，我们假设miR-21降低了ENDS诱导的细胞凋亡。 通过防止ENDS衍生的醛和尼古丁激活巨噬细胞来预防动脉粥样硬化。 为了验证这一假设，我们将1）检查电子烟对动脉粥样硬化的影响。在低密度脂蛋白受体- 空小鼠暴露于过滤空气，不同比例的丙二醇（PG）：植物甘油 (VG)，PG：VG +尼古丁和JUUL特定的电子液体，我们将量化时间，剂量和性别- 动脉粥样硬化病变形成的依赖性变化。我们将研究如何结束和他们的 成分影响菌斑的组成、性质和稳定性; 2）描绘 ENDS衍生的醛类的致动脉粥样硬化作用。我们将研究是否淬火e- 液体和ENDS衍生的醛，通过口服肌肽或巨噬细胞特异性 肌肽合酶的过表达防止巨噬细胞活化和动脉粥样硬化形成， miR-21如何调控这些过程; 3）阐明ENDS衍生的动脉粥样硬化性， 尼古丁。我们将探讨ENDS如何激活巨噬细胞α 7 nAChR，以及巨噬细胞特异性 α 7 nAChR缺乏影响ENDS诱导的巨噬细胞活化和动脉粥样硬化形成我们将 我们还研究了miR-21如何调节这些过程。总体而言，拟议的研究将建立 ENDS诱导的动脉粥样硬化的新动物模型，并描述了潜在的化学物质， 毒性的细胞和分子机制。

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.