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2017 Cardiovascular Research Day Abstract Book

29 SAA is not Just an

29 SAA is not Just an HDL-Associated Lipoprotein Patricia Wilson, MS 1 • Joel Thompson, PhD 1 • Frederick de Beer, MD, PhD 1 • Nancy Webb, PhD 1 • Lisa Tannock, MD, PhD 2 1Saha Cardiovascular Research Center, University of Kentucky • 2 Endocrinology/Saha Cardiovascular Research Center, University of Kentucky Staff Cardiovascular disease (CVD) is the leading cause of death in developed nations despite widespread use of pharmacological interventions. Individuals with obesity and/or diabetes are at particularly high risk for CVD and research suggests this may be due to elevated levels of serum amyloid A (SAA). Brief and chronic elevations of SAA have been indeed found to be atherogenic in mouse models. The current dogma is that SAA is exclusively an HDL associated lipoprotein. However, we and others have reported SAA on apoB-containing lipoproteins in both humans and mice and several studies have recently suggested that SAA-LDL is a risk factor for CVD. The goal of this study was to determine if SAA can shift between HDL and apoB-containing particles, and if the presence of SAA on apoB particles affects their atherogenicity. To determine if SAA could be exchanged between lipoproteins in vitro, we first incubated SAA with each lipoprotein separately, then mixed the lipoprotein containing SAA with each of the other two lipoproteins. To determine is this exchange could also occur in vivo, we injected apoE-/- x SAA1.1/2.1-DKO mice with murine SAA complexed with individual murine lipoproteins. To elucidate the role of CETP in SAA shifting, some mice were preinjected with an adenovirus expressing CETP 72 hours prior to injection with SAA- HDL. We now have evidence that SAA does indeed shift between lipoproteins both in vitro and in vivo, facilitated by CETP, and that delipidated SAA will completely associate with any available lipoproteins although preferentially on HDL. The presence of SAA on apoB-containing lipoproteins has physiological relevance, as we have demonstrated that this augments the proteoglycan binding affinity of these particles thus increasing their atherogencity. Collectively our data shows that SAA can be exchanged from HDL to apoB-containing lipoproteins and that this exchange is proatherogenic. 45

30 Computational modeling of amylin-induced calcium dysregulation in rat ventricular cardiomyocytes Peter Kekenes-Huskey 1 1Chemistry, University of Kentucky Faculty Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4, 5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentrationdependent manner [5], which is correlated with elevated cytosolic Ca 2+ . These findings motivate our core hypothesis that non-selective inward Ca 2+ conduction afforded by human amylin oligomers increase cytosolic and SR Ca 2+ load, which thereby magnifies intracellular Ca 2+ transients. Questions remain however regarding the mechanism of amylin-induced Ca 2+ dysregulation, including whether enhanced SL Ca 2+ influx is sufficient to elevate cytosolic Ca 2+ load [6], and if so, how might amplified Ca 2+ transients perturb Ca 2+ -dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca 2+ signaling to reflect experimentally-measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca 2+ transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca 2+ loading of the sarcoplasmic reticulum (SR) and the greater fractional release may contribute to the Ca 2+ -dependent activation of calmodulin. Importantly, elevated Ca 2+ in the SR and dyadic space collectively drive greater fractional SR Ca 2+ release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca 2+ transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca 2+ dysregulation in prediabetes. 46

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