A 6-month systems toxicology inhalation study in ApoE-/- mice demonstrates reduced cardiovascular effects of E-vapor aerosols compared to cigarette smoke

Smoking cigarettes is harmful to the cardiovascular system. Considerable attention has been paid to the reduced harm potential of alternative nicotine-containing inhalable products such as e-cigarettes. We investigated the effects of E-vapor aerosols or cigarette smoke (CS) on atherosclerosis progression, cardiovascular function, and molecular changes in the heart and aorta of female ApoE-/- mice. The mice were exposed to aerosols from three different E-vapor formulations: (1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine) or (3) test (base and flavor) or to CS from 3R4F reference cigarettes for up to 6 months. Concentrations of CS and base or test aerosols were matched at 35 µg nicotine/L. Exposure to CS, compared with sham-exposed fresh air controls, accelerated atherosclerotic plaque formation, while no such effect was seen for any of the three E-vapor aerosols. Molecular changes indicated disease mechanisms related to oxidative stress and inflammation in general, plus changes in calcium regulation, and altered cytoskeletal organization and microtubule dynamics in the left ventricle. While ejection fraction, fractional shortening, cardiac output, and isovolumic contraction time remained unchanged following E-vapor aerosols exposure, the nicotine-containing base and test aerosols caused an increase in isovolumic relaxation time similar to CS. A nicotine-related increase in pulse wave velocity and arterial stiffness was also observed, but it was significantly lower for base and test aerosols than for CS. These results demonstrate that in comparison with CS, E-vapor aerosols induce substantially lower biological responses associated with smoking-related cardiovascular diseases.吸烟对心血管系统具有损害作用。诸如电子烟（e-cigarettes）这类含尼古丁的可吸入替代产品，其减害潜力已受到广泛关注。本研究探究了电子烟雾（E-vapor aerosols）或卷烟烟气（cigarette smoke, CS）对雌性载脂蛋白E基因敲除（ApoE-/-）小鼠动脉粥样硬化进展、心血管功能以及心脏与主动脉分子变化的影响。实验小鼠分别暴露于三种不同配方的电子烟雾：(1) 载体基质（丙二醇与植物甘油）、(2) 基础基质（载体基质与尼古丁）或(3) 测试基质（基础基质与调味剂），同时设置暴露于3R4F标准参考卷烟烟气的对照组，暴露时长最长达6个月。卷烟烟气与基础、测试基质电子烟雾的尼古丁浓度均统一设置为35 µg/L。与假暴露组（仅暴露于新鲜空气）相比，暴露于卷烟烟气会加速动脉粥样硬化斑块的形成，而三种电子烟雾均未出现此类效应。分子层面的变化显示，总体而言存在与氧化应激及炎症相关的疾病机制，此外还观察到左心室的钙调节异常、细胞骨架组织改变以及微管动力学变化。尽管暴露于电子烟雾后，小鼠的射血分数、短轴缩短率、心输出量及等容收缩时间均未发生显著变化，但含尼古丁的基础与测试基质电子烟雾可使等容舒张时间延长，该效应与卷烟烟气暴露后的结果相似。研究还观察到尼古丁相关的脉搏波速度与动脉僵硬度升高，但基础与测试基质电子烟雾的该效应显著低于卷烟烟气组。上述结果表明，与卷烟烟气相比，电子烟雾所诱导的与吸烟相关心血管疾病的生物学效应显著更低。