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2017 Cardiovascular Research Day Abstract Book

85 Oxidized neutral

85 Oxidized neutral lipid lipolysis as a novel regulator of insulin signaling during acute stress Katelyn Ahern 1 • Garrett Mullins, PhD 1 • Vidisha Raje, PhD 1 • Vlad Serbulea 1 • Norbert Leitinger, PhD 1 • Thurl Harris, PhD 1 1Pharmacology, University of Virginia Graduate Student The acute stress response following an injury or surgery often results in systemic insulin resistance (IR) and hyperglycemia which can lead to increased morbidity and mortality. Post-operative IR is downstream of stress hormones such as catecholamines, but the underlying mechanisms driving IR are unknown, thus limiting therapeutic development. We have previously demonstrated that β- adrenergic stimulation of adipocytes causes inhibition of the mTOR complexes and leads to the development of IR in a lipolysis-dependent manner. Therefore, we hypothesize that a product of lipolysis is responsible. We find that lipid extracts isolated from forskolin-stimulated 3T3-L1 adipocytes inhibit the activity of the mTOR complexes in vitro. However, when tested, “traditional” products of lipolysis had no effect on mTOR complexes. Interestingly, stimulating oxidation of fatty acids using tert-butyl hydroperoxide further exacerbates mTOR inhibition, while antioxidant treatment reverses this effect, suggesting that the active species is an oxidized fatty acid. In fact, incubation of mTOR complex with in vitro auto-oxidized fatty acids is sufficient to inhibit kinase activity. These findings reveal a previously unrecognized mechanism of oxidized fatty acid signaling and mTOR complex regulation in the development of peripheral IR during acute stress. Our future work will focus on identifying these species in vivo using our novel targeted liquid chromatography-mass spectrometry method and characterizing their physiological role in response to stress-inducing events known to stimulate reactive oxygen species production. 101

86 Pharmacological inhibition of HuR improves survival and reduces adverse cardiac remodeling following left-ventricular pressure overload Sarah Anthony 1 • Xiaoqing Wu, PhD 2 • Lisa Green 1 • Michelle Nieman 3 • John Lorenz, PhD 3 • Jack Rubinstein, MD 1 • Liang Xu, PhD 2 • Michael Tranter, PhD 1 • Burns Blaxall, PhD 4 1Division of Cardiovascular Health and Disease, University of Cincinnati • 2 Molecular Biosciences, University of Kansas • 3 Pharmacology and Systems Physiology, University of Cincinnati • 4Department of Pediatrics, Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Staff Human antigen R (HuR) is a widely expressed RNA binding protein that has been implicated in numerous human diseases including cancer, neurological disorders, and cardiovascular disease. We have previously shown that HuR is both necessary and sufficient for induction of hypertrophic signaling pathways in isolated primary myocytes. In addition, data from our lab is the first to suggest that HuR expression and activation is increased in failing human hearts. To determine the role of HuR in hypertrophic signaling in vivo, we created an inducible cardiomyocyte-specific HuR deletion mouse, and showed that genetic deletion of HuR reduces pathology using a transverse aortic constriction (TAC) model of pressure-overload-induced hypertrophy, adverse cardiac remodeling, and heart failure. In this work, we sought to recapitulate this reduction in pathology using KH-3, a novel pharmacological inhibitor of HuR, to determine the translational potential of HuR inhibition as a viable therapeutic target. Twenty wild-type mice were randomized to either vehicle or KH-3 at four weeks post-TAC, a timepoint consistent with substantial development of cardiac hypertrophy, and monitored via serial echocardiography for a further seven weeks. Our results show that treatment with KH-3 increased survival relative to vehicle controls. In addition, as compared with vehicle, KH-3 treatment significantly abated the continued progression of left ventricular (LV) hypertrophy. This was accompanied by a significant preservation of LV ejection fraction and reduction in LV chamber dilation in KH-3 treated mice. Importantly, chronic KH-3 treatment had no effects on systemic blood pressure and no observable adverse reactions. In conclusion, these results suggest that inhibition of HuR is a promising therapeutic approach to treat pathological LV hypertrophy. 102

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