Determining the role of free fatty acids in developing e-cigarette-induced cardiac dysfunction

项目概要/摘要： 电子烟（电子烟）作为一种替代品在全球范围内变得非常受欢迎。 传统的尼古丁香烟，无论是在吸烟者和从未吸烟的人。脂肪组织可以改变 通过分泌游离脂肪酸、脂肪因子和生物活性分子来维持心脏的功能，从而使其成为 全身代谢的关键内分泌调节剂。电子烟可诱导脂肪组织脂解 产生游离脂肪酸（FFA）的释放。FSP 27是一种脂滴相关蛋白，具有抗脂肪分解作用。 行动上FFA是引起脂毒性和氧化应激的充分表征的因子。氧化应激 在功能失调的心脏的炎症、代谢和收缩变化中起重要作用。CD36 受体在使脂肪酸转运到心脏中起作用。EP 80317，一种CD 36的配体，降低心肌细胞的 脂肪酸摄取和心脏保护。 在我们的初步数据中，我们检测了一种抗高血压药物阿昔莫司（acipimox）对脂肪分解的影响， 电子烟导致心脏功能障碍。为了研究电子烟对心脏的影响，我们使用C57 BL/6小鼠， 高脂饮食，一种常用的小鼠模型，用于研究心脏代谢疾病。将小鼠暴露于盐水中， 电子烟与尼古丁（2.4%），或电子烟（2.4%）加阿昔莫司12周。分数缩短和 与生理盐水和e-cig（2.4%）+相比，暴露于e-cig的小鼠的射血分数降低（2.4%）。 阿昔莫司。因此，阿昔莫司挽救了电子烟引起的心功能不全。暴露于e- 香烟增加了M-CSF、IL-6和FFA的循环水平，其通过阿昔莫司正常化。HO- 1，一种氧化应激标志物，与盐水相比，暴露于电子烟的小鼠心脏中增加。 然而，电子烟（2.4%）+阿昔莫司组的HO-1水平正常。此外，脱嘌呤/脱嘧啶（AP） 暴露于电子烟的小鼠心脏中的DNA损伤的一种表现，增加了2.4%， 生理盐水组来自用阿昔莫司处理的小鼠的心脏的AP位点水平与盐水组相似。 因此，阿昔莫司可使电子烟引起的心功能障碍正常化，并使炎症反应正常化。 电子烟诱导的表型。在这项研究中，我们的具体目标是：目标1将评估是否脂肪细胞- FSP 27的特异性过表达可预防电子烟诱导的心脏功能障碍。目标2将决定 EP 80317，一种抑制脂肪酸摄取的CD 36选择性配体，是否赋予心脏保护作用， 电子烟引起的心功能障碍模型。了解血清游离脂肪酸升高对e- 烟草引起的心脏功能障碍对于遏制电子烟对心脏的有害影响至关重要。

Project Summary/Abstract: Electronic cigarettes (e-cigarettes) are becoming exceptionally popular worldwide as an alternative to conventional nicotine cigarettes, both in smokers and people who have never smoked. Adipose tissue can alter the heart's function via the secretion of free fatty acids, adipokines, and bioactive molecules, thus making it a critical endocrine regulator of whole-body metabolism. E-cigarettes can induce lipolysis in adipose tissue producing the release of free fatty acids (FFAs). FSP27 is a lipid droplet-associated protein with anti-lipolytic action. FFAs are a well-characterized factor for causing lipotoxicity and oxidative stress. Oxidative stress plays a significant role in the inflammatory, metabolic and contractile changes of the dysfunctional heart. The CD36 receptor plays a role in enabling fatty acid transport to the heart. EP80317, a ligand to CD36, reduces myocardial fatty acid uptake and is cardioprotective. In our preliminary data, we examined the effects of an antihyperlipidemic drug, acipimox, that blocks lipolysis on e-cigarettes induced cardiac dysfunction. To study the cardiac effect of e-cigarettes, we used C57BL/6 mice on a high-fat diet, a commonly used murine model, to study cardiometabolic disease. Mice were exposed to saline, e-cigarettes with nicotine (2.4%), or e-cigarette (2.4%) plus acipimox for 12 weeks. Fractional shortening and ejection fraction was decreased in mice exposed to e-cig (2.4%), compared with saline and e-cig (2.4%) + acipimox. Therefore, acipimox rescued the e-cigarette-induced cardiac dysfunction. Mice exposed to e- cigarettes have increased circulating levels of M-CSF, IL-6, and FFAs, which were normalized by acipimox. HO- 1, an oxidative stress marker, was increased in the hearts of mice exposed to e-cigarettes compared to saline. However, HO-1 levels in the e-cig (2.4%)+ acipimox group were normal. Moreover, apurinic/apyrimidinic (AP) sites, a manifestation of DNA damage, were increased in the hearts of mice exposed to e-cig (2.4%) compared to the saline group. AP sites levels of hearts from mice treated with acipimox were similar to the saline group. Therefore, acipimox normalizes the e-cigarettes-induced cardiac dysfunction and normalizes the inflammatory phenotype induced by e-cigarettes. In this study, our specific aims are: Aim 1 will evaluate whether adipocyte- specific overexpression of FSP27 prevents e-cigarette-induced cardiac dysfunction. Aim 2 will determine whether EP80317, a CD36-selective ligand that inhibits fatty acids uptake, confers a cardioprotective effect in the e-cigarette-induced cardiac dysfunction model. Understanding the impact of elevated serum FFAs on e- cigarettes-induced cardiac dysfunction will be crucial to curb the detrimental cardiac effects of e-cigarettes.