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.