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2017 Cardiovascular Research Day Abstract Book

15 Atherosclerosis in

15 Atherosclerosis in the Cerebrovasculature of Nonhuman Primates Promotes Reactive Gliosis: A Potential Model for Vascular Dementia Peter Hecker 1 • Lei Cai, PhD 1 • Elizabeth Head, PhD 2 • Donna M. Wilcock, PhD 3 • Ryan Temel, PhD 1 1Saha Cardiovascular Research Center and Department of Pharmacology and Nutritional Sciences, University of Kentucky • 2 Sanders-Brown Center of Aging and Department of Pharmacology and Nutritional Sciences, University of Kentucky • 3 Sanders-Brown Center of Aging and Department of Physiology, University of Kentucky Graduate Student Age- and lifestyle-dependent vascular insults drive and/or exacerbate cardio- and cerebro- vascular disease. While several animal models exist for studying vascular contributions to cardiovascular disease there are few models for studying the vascular contributions to cognitive impairment and dementia (VCID). Our lab is studying atherosclerosis progression and regression in male cynomolgus monkeys fed a high-fat/high-cholesterol diet. After 20 months on the atherogenic diet, a subset of monkeys are switched to standard nonhuman primate “chow” diet and are concomitantly treated with vehicle or a microRNA-33 antagonist (anti-miR-33). We hypothesize that anti-miR-33 treatment will create more stable atherosclerotic plaques by increasing cholesterol efflux from foam cells and dampening inflammation in the artery wall. While our initial interest was atherosclerosis in the coronary arteries, we have recently turned our attention to atherosclerosis in the main arterial network that supplies the brain. Evaluation of the circle of Willis (COW) revealed the presence of atherosclerotic plaques in major branch points of the large arteries. Immunohistochemistry (IHC) on arterial sections has begun to evaluate the size and molecular/cellular composition of these atherosclerotic plaques. Understanding that atherosclerosis could reduce cerebral blood flow (CBF) and/or promote endothelial dysfunction, we have started to examine brain sections from our monkeys for underlying neuropathology. Preliminary IHC data shows increased microglia and astrocyte reactivity around small cerebral vessels from a monkey with atherosclerosis versus a healthy, control animal. The marked increase in glial reactivity around small vessels may suggest extravasation or decreased CBF, both capable of driving neuroinflammation and downstream neurodegeneration. In the near future, we plan to pair MRI analysis of hypoperfusion and white matter lesions (WML) with histology and IHC assessments of WML, cerebral amyloid angiopathy, and astrocyte endfeet engagement with the vasculature. Although much work remains to be done, we are optimistic that we have created a unique and important translational model that mimics human cerebrovascular atherosclerosis and neuropathology associated with VCID. 31

16 Hypercholesterolemia Induces Acute Thymic Atrophy Through Blocking Thymocyte Differentiation and Expansion Xiang Ye, PhD 1 • XiangAn Li, PhD 1 1Saha Cardiovascular Research Center, University of Kentucky Postdoc Background: Thymus is the primary site for T cell development, however its function is decreasing with age, defined as thymic involution. The age-related thymic atrophy reduces the ability to produce naïve T cells, which is one of the main factors contributes to lower immune-surveillance in the elderly. Other than aging, thymic atrophy also can be accelerated by various stressors, like chemotherapy, corticosteroids, disturbed lipid metabolism, infection, inflammation and psychological stress. However, our knowledge on thymic atrophy is very limited. Here we report that hypercholesterolemia induces acute thymic atrophy through inhibiting thymocyte expansion and differentiation. Methods and Results: To investigate the role of hypercholesterolemia, we use albumin driven cre to specifically knock out SRBI in the liver, causing defect in reverse cholesterol transport and thus hypercholesterolemia. One week of HCD induces acute thymic atrophy (thymus weight: SRBIflox/flox vs SRBIflox/flox-Alb-Cre, 28.22mg vs 9.28mg, p < 0.0001) in RCT defected mice, and a more dramatic decrease of thymocyte cellularity (5.9 X 10E7 vs 4.5 X 10E6). In order to know what happened with T cell development, we profiled development process using flowcytometry with CD4, CD8a, CD44 and CD25. We found that CD4+CD8a+ cell decreases to be only 18% of thymocyte from more than 80%, which indicates blocks in thymocyte differentiation. Besides, we also see an increase of DN1 (CD4-CD8a-CD25-CD44+) progenitor cells increased from 17% to 38% of double negatives (CD4-CD8a-). To exclude the possibility of accelerated cell apoptosis of certain cell type rather than ceased differentiation, we measured thymocyte apoptosis using annexin V staining. The results only show a very mild increase in cell apoptosis (annexin V+: 8% vs 11%) after 3 days of HCD treatment, which could not explain the dramatic change in thymocytes numbers alone. Then we performed gene expression profile on the thymus from mice after 3 days of HCD. Gene enrichment analysis using the differentially expressed genes reveals an enrichment of cell cycle genes, with many cell cycle-promoting genes decreased and cell cycle inhibiting genes increased. Consistently, BrdU incorporation combined with 7-AAD staining also indicates impaired thymocyte proliferation, the thymocytes reside in G2-M phase decrease from 2.8% to 1.7% of total thymocytes. The earlier developing cells are most impacted, with G2-M cells decrease from 5.3% to 1.4% of DN. Conclusions: Hypercholesterolemia induces acute thymic atrophy through inhibiting thymocyte expansion and differentiation. This study indicates high cholesterol diet could exert its impact on immune system through accelerating thymic atrophy. 32

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