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2017 Cardiovascular Research Day Abstract Book

37 Elevated circulating

37 Elevated circulating TGF-beta is not the cause of increased atherosclerosis development in biglycan deficient mice Joel Thompson, PhD 1 • Patricia Wilson, PhD 1 • Alex Wyllie 1 • Adrian Wyllie 1 • Lisa Tannock, MD 1 1Internal Medicine, University of Kentucky Staff Background: Vascular biglycan contributes to atherosclerosis development and increased biglycan expression correlates with increased atherosclerosis. However, mice deficient in biglycan have either no reduction in atherosclerosis or an unexpected increase in atherosclerosis. Biglycan deficient mice have systemically elevated TGF-beta, likely due to lack of sequestration of TGF-beta in extracellular matrix The purpose of this study was to determine if prevention of TGF-beta elevations in biglycan deficient mice affected atherosclerosis development. Methods: Biglycan deficient mice were crossed to Ldlr deficient mice. Diabetes was induced via streptozotocin and all mice were fed a high cholesterol diet. Diabetic biglycan wildtype and biglycan deficient Ldlr deficient mice were injected with the TGF-beta neutralizing antibody 1D11 or irrelevant control antibody 13C4. Results: Biglycan deficient mice had significantly elevated plasma TGF-beta levels, which was further increased by diabetes, and significantly increased atherosclerosis. There was a significant correlation between TGF-beta concentrations and atherosclerosis. However, despite nearly complete suppression of plasma TGF-beta levels in mice treated with the TGF-beta neutralizing antibody 1D11, there was no significant difference in atherosclerosis between mice with elevated TGF-beta levels and mice with suppressed TGF-beta levels. Conclusions: The increased atherosclerosis in biglycan deficient mice does not appear to be due to elevations in TGF-beta. 53

38 Gestational Diabetes Provokes Postpartum Cardiac Hypertrophy via Activation of Ca2+- Dependent Signaling Amanda Hoskins 2 • Nirmal Verma, PhD 1 • Florin Despa, PhD 1 • Sanda Despa, PhD 1 1Pharmacology & Nutritional Sciences, University of Kentucky • 2 University of Kentucky Undergraduate Introduction: Gestational diabetes mellitus (GDM) complicates 9% of pregnancies in the US and its incidence is growing. Women with prior GDM have higher risk of developing cardiac hypertrophy and dysfunction, but the underlying mechanisms are largely unknown. Hypothesis: GDM promotes pathological growth of the heart through Ca2+-dependent hypertrophy signaling. Methods and Results: Female rats that express the human isoform of amylin, an amyloidogenic peptide co-secreted with insulin, in the pancreatic β-cells (HIP rats) were used as a GDM model. WT littermates served as controls. In both groups, glucose tolerance decreased during pregnancy and recovered after giving birth, with HIP females remaining glucose intolerant compared to the WT throughout the study. Cardiac hypertrophy, assessed from heart weight-to-body weight ratio, heart weight-to-tibia length ratio and echocardiographic measurements of the left-ventricular wall, occurred in both HIP and WT females during pregnancy. By two months postpartum, heart size returned to the pre-pregnancy level in the WT but remained significantly larger in HIP females. To uncover the cause of hypertrophy in postpartum HIP females, we investigated the activation status of calcineurin/NFAT and CaMKII/HDAC hypertrophy pathways. Calcineurin/NFAT signaling, assessed from the nuclear-to-cytosolic localization of NFATc4, was reduced during late pregnancy in both groups. In WT females, this pathway returned to its baseline activation level within two months postpartum. However, in postpartum HIP females the ratio of nuclear-to-cytosolic NFATc4 was significantly larger than at baseline, indicating re-activation of this hypertrophy pathway. In contrast, the CaMKII/HDAC hypertrophy signaling was strongly activated in late pregnancy and returned to baseline postpartum in both HIP and WT females. Since calcineurin and CaMKII are activated by higher cytosolic Ca2+, we also analyzed myocyte Ca2+ cycling. Ca2+ transient decay was slower in myocytes from postpartum HIP females vs. baseline, while no differences occurred in the WT. Conclusion: Two months after a GDM-complicated pregnancy, female rats show cardiac hypertrophy that is likely caused by activation of calcineurin/NFAT hypertrophy pathway. 54

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