E-cigarette aerosol effects on the cardiovascular system in rodents

项目概要： 电子烟气溶胶含有反应性醛，包括乙醛、甲醛和丙烯醛， 可高度扩散到细胞中。这些活性醛也存在于烟草和酒精中， 导致细胞损伤从而导致心血管疾病。此外，世界上约有5.6亿人 携带乙醛脱氢酶2（ALDH 2）遗传变异ALDH 2 *2，严重限制了 反应性醛，例如存在于电子烟气溶胶中的那些。具有ALDH 2 *2变体增加了 心血管疾病的风险，包括心脏病发作造成的细胞损伤。然而，很少有人知道， 电子烟气溶胶中的反应性醛水平，再加上反应性醛中存在的这种遗传差异， 醛代谢，影响心血管生理和细胞功能。 在这里，我们将研究电子烟气雾剂对心血管系统的影响， 使用野生型ALDH 2或ALDH 2 *2变体敲入小鼠的电子烟气溶胶中的反应性醛。我们 将通过（AIM 1）将野生型ALDH 2小鼠和ALDH 2 *2基因敲入小鼠暴露于电子烟气雾剂， 通过远程遥测监测心脏，并在心脏和肺中量化e- 香烟烟雾暴露在分离的成人心肌细胞（AIM 2）中，我们将确定野生型ALDH 2 和ALDH 2 *2基因敲入小鼠，电子烟气雾剂中的单个反应性醛如何改变细胞蛋白质 加合物形成和细胞功能。我们还将确定反应性醛的水平存在于 电子烟气溶胶对心肌细胞缺氧-复氧损伤的影响。人脐静脉 内皮细胞和分离的肺原代内皮细胞（AIM 3），我们还将确定如何反应 醛暴露引起蛋白质加合物形成和线粒体功能的变化， 内皮细胞功能障碍 我的研究团队可以为这个领域带来特定的技能和独特的工具。我们将进行研究， 电子烟气溶胶和气溶胶中存在的反应性醛如何影响心血管系统。 特别是，这些研究将解决暴露于电子烟气雾剂的心血管影响， 研究电子烟气溶胶暴露对心肌细胞和内皮细胞的影响。

PROJECT SUMMARY: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein which are highly diffusible into cells. These reactive aldehydes, also found in tobacco cigarettes and alcohol, are known to cause cellular damage that can lead to cardiovascular disease. Further, ~560 million people in the world carry an aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2, that severely limits the metabolism of reactive aldehydes such as those present in e-cigarette aerosol. Having an ALDH2*2 variant increases the risk for cardiovascular disease, including cellular damage from a heart attack. However, little is known how the reactive aldehyde levels in e-cigarette aerosol, coupled with this genetic difference present in reactive aldehyde metabolism, effect cardiovascular physiology and cellular function. Here, we will study the effects on the cardiovascular system of e-cigarette aerosol in addition to the individual reactive aldehydes within e-cigarette aerosol using wild type ALDH2 or ALDH2*2 variant knock-in mice. We will do so by (AIM 1) exposing wild type ALDH2 mice and ALDH2*2 knock-in mice to e-cigarette aerosol while monitoring the heart by remote telemetry and quantifying in the heart and lungs the biochemical effects of e- cigarette aerosol exposure. In isolated adult cardiac myocytes (AIM 2), we will determine in wild type ALDH2 and ALDH2*2 knock-in mice how the individual reactive aldehydes in e-cigarette aerosol alter cellular protein adduct formation and cellular function. We will also determine how reactive aldehydes at the levels present in e-cigarette aerosol affect cardiac myocytes subjected to hypoxia-reoxygenation injury. In human umbilical vein endothelial cells and isolated lung primary endothelial cells (AIM3), we will also determine how reactive aldehyde exposure causes changes in protein adduct formation and mitochondrial function that leads to endothelial cell dysfunction. My research team can bring specific skill-sets and unique tools to this field. We will perform studies to uncover how e-cigarette aerosol and the reactive aldehyde present within the aerosol effect the cardiovascular system. In particular, these studies will address the cardiovascular effects of exposure to e-cigarette aerosol and investigate the effects of e-cigarette aerosol exposure on cardiac myocytes and endothelial cells.