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2017 Cardiovascular Research Day Abstract Book

5 Potential Role of

5 Potential Role of Muscle Specific Ribosomal Protein L3-like in Cardiomyocyte Transverse Tubule Formation Laura Peterson 1 • Alexander Alimov, PhD 1 • Jon Satin, PhD 1 • Brian Delisle, PhD 1 • John McCarthy, PhD 1 1Physiology, University of Kentucky Graduate Student Ribosomes have long been thought as serving in a constitutive housekeeping function and possess no real regulative capacity. Recently however, ribosomal proteins have been shown to provide the ribosome with a regulatory capacity across phyla. Ribosomal protein paralogs arose from a duplication event millions of years ago and have contributed to the development of ribosome specialization. By allowing a ribosome to function in its original capacity and acquire new roles, some ribosomal protein paralogs have acquired specialized roles. Ribosomal protein L3-like (RPL3- like) is expressed only in skeletal muscle and the heart but its paralog, RPL3, is found ubiquitously throughout the body. Strikingly, the expression in the heart is limited to the ventricles and is not expressed in the atria. One of the major anatomical differences in the atria and ventricle is the patterning of transverse tubules (t-tubules) with the ventricles exhibiting a highly symmetrical, regular transverse pattern and the atria having an irregular pattern with more prominent axial projections. RPL3-like knock out in the adult mouse disrupts ventricular t-tubule organization. We hypothesize that RPL3-like containing ribosomes preferentially associate with transcripts that encode for proteins involved in t-tubule formation thereby controlling morphology. 21

6 Serum Amyloid A Activates the NLRP3 Inflammasome in Macrophages Preetha Shridas, PhD 1 • Maria de Beer, PhD 2 • Nancy Webb, PhD 3 1Internal Medicine, University of Kentucky • 2 Physiology, University of Kentucky • 3 Molecular and Biomedical Pharmacology, University of Kentucky Faculty Objectives: Interleukin-1beta (IL-1β) has been implicated in many chronic diseases including atherosclerosis and type 2 diabetes. Production of bioactive IL-1β is controlled by the inflammasome, a multi-protein complex that regulates caspase-1 activity. Serum Amyloid A (SAA) is an acute-phase protein whose levels in circulation can increase more than 1000-fold during severe infection and tissue damage. SAA is more modestly elevated in conditions associated with chronic inflammation, including obesity. SAA has been identified as the first known physiological mediator capable of activating the NRLP3 inflammasome. The objective of this study is to investigate the mechanisms involved in SAA-mediated inflammasome activation in macrophages. Methods/Results: J774 macrophage-like cells and mouse bone-marrow derived macrophages (BMM) were stimulated with 5-25 µg/ml purified lipid-free mouse SAA, concentrations corresponding to those typically observed in obese individuals. The analyses of culture media and cell lysates demonstrated that SAA dose-dependently induced both caspase-1 activation and IL-1β secretion. The ability of SAA to induce IL-1β secretion was significantly reduced in BMM deficient in NRLP3. There was significant suppression in IL-1β secretion by SAA when J774 cells were treated with SAA in the presence of caspase-1inhibitor, Z-YVAD-FMK. A P2X7-receptor antagonist, AA38079, did not have any effect on SAA-mediated IL-1β production. Inhibition of reactive oxygen species (ROS) and cathepsin-B activation by N-acetyl-L-cysteine and CA-074, respectively, inhibited inflammasome activation by SAA. Inhibiting cellular potassium efflux by glyburide also significantly reduced SAA-mediated IL-1β secretion. Pre-incubating SAA with HDL prior to cell treatments completely inhibited its ability to trigger inflammasome activation. HDL also abrogated SAAmediated ROS generation in J774 cells. Conclusions: SAA-mediated NRLP3 inflammasome activation in macrophages is dependent on ROS generation, release of cathepsin-B, and potassium efflux, and is independent of the P2X7 receptor. Ongoing studies are investigating the cellular receptor(s) involved and the mechanism by which lipoproteins mask SAA’s effects. Blocking SAA-mediated inflammasome activation may ameliorate increased risk for type 2 diabetes and atherosclerosis in obese individuals. 22

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