Targeting PARP Proteins in electronic cigarettes-induced cardiac dysfunction - : Project Summary Electronic cigarettes (e-cigarettes) are becoming exceptionally popular worldwide as an alternative to conventional cigarettes. Nicotine can induce lipolysis, leading to increased free fatty acids (FFAs) in the blood. Increased levels of FFAs are one of the key elements in inducing lipotoxicity, mitochondrial dysfunction, and DNA damage. NAD+ homeostasis is regulated by nutrient-sensing signaling and DNA damage response pathways, which play key roles in metabolism and survival. Poly (ADP-ribose) polymerases 1 (PARP1) and Sirtuin-1 have a common co-factor, NAD+. Therefore, increased PARP1 activity can impact Sirtuin-1 activity by reducing the NAD+ pool. We investigated the effects of acipimox, an antihyperlipidemic drug, on e-cigarettes-induced cardiac dysfunction. C57BL/6J wild-type mice on high fat diet were exposed to saline, e-cigarettes with nicotine (2.4%) [e-cig (2.4%)], 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 acipimox. Therefore, acipimox rescued the e-cigarette-induced cardiac dysfunction. Transcriptomic evaluation with Gene Set Enrichment Analysis revealed that e-cigarette-treated mice had genes enriched in the G2/M DNA damage checkpoint pathways. These changes were normalized by acipimox. Mice exposed to e-cigarettes have increased circulating levels of inflammatory cytokines and FFAs, which were regularized by acipimox. Moreover, mice exposed to e-cig (2.4%) had increased apurinic/apyrimidinic sites and PARP1 activity. These manifestations of DNA damage were normalized by acipimox. Aim 1 will test the hypothesis that PJ34, a potent inhibitor of PARP proteins, reverses oxidative stress, mitochondrial abnormalities, and cardiac dysfunction induced by e-cigarettes. Aim 2 will elucidate if genetically increasing SIRT1 levels in cardiomyocytes can prevent the development of e-cigarette-induced cardiac dysfunction. Aim 3 will assess the role of lipolysis on e-cigarette-induced cardiac dysfunction with an inhibitor of adipose triglyceride lipase, atglistatin. PARP1 pathway might be a useful therapeutic target to counteract the detrimental cardiac effects of e-cigarettes. Understanding the consequences of e-cigarette use on cardiac dysfunction and DNA damage response is directly relevant to the development of policies related to tobacco use.
