cleavage of the extracellular domain from tissue endoglin. Soluble endo- glin was proposed to be a marker or a possible cause of endothelial dysfunction in ...
Abstracts / Atherosclerosis 235 (2014) e84–e191
the endothelial-leukocyte interactions even in the absence of increased lipid concentrations. 13 - Endothelial cells and function EAS-0825. ACTIVATION OF CELL SURFACE GRP78 BY ANTI-GRP78 AUTOANTIBODIES AUGMENTS ENDOTHELIAL CELL ACTIVATION AND ACCELERATES ATHEROSCLEROTIC LESION DEVELOPMENT E. Crane, R.C. Austin Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada Objectives: Damage to the endothelium is an important contributor to the initiation and progression of atherosclerosis. GRP78 is an endoplasmic reticulum (ER)-resident molecular chaperone in normal healthy endothelium that functions to assist in the correct folding of newly synthesized proteins and to prevent aggregation of folding intermediates. In contrast, GRP78 is also present as a transmembrane protein on the surface of lesionresident endothelial cells. Surface GRP78 is known to act as a surface signaling receptor in cancer cells and is activated by anti-GRP78 autoantibodies isolated from the serum of cancer patients. However, the role of anti-GRP78 autoantibody activation of cell surface GRP78 in atherosclerosis is unknown. The objective of this study is to determine the effect of anti-GRP78 autoantibodies on endothelial cells and whether engagement of cell surface GRP78 contributes to lesion development. Methods: apoE-/- mice were immunized against recombinant GRP78 to induce high titers of anti-GRP78 autoantibodies, as measured by ELISA. Serial sections at the aortic root were assessed by immunohistochemistry. Results: Here we show that apoE-/- mice with advanced atherosclerotic lesions have elevated serum levels of anti-GRP78 autoantibodies compared to age-matched C57BL/6 mice. Furthermore, apoE-/- mice immunized against recombinant GRP78 demonstrated a significant increase in anti-GRP78 autoantibody titers as well as accelerated lesion growth compared to control immunized apoE-/- mice. Conclusion: Our results suggest that signaling through cell surface GRP78 can activate intracellular pathways that augment atherosclerotic lesion development. These findings provide a starting point for understanding the role of anti-GRP78 autoantibodies and the activation of surface GRP78 in endothelial cell function and lesion development. Furthermore, inhibiting the interaction of anti-GRP78 autoantibodies with cell surface GRP78 could present a novel therapeutic strategy to modulate lesion growth, thereby reducing the risk for atherosclerosis and cardiovascular disease. 13 - Endothelial cells and function EAS-0458. ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH METABOLIC SYNDROME ALONE AND PATIENTS WITH METABOLIC SYNDROME AND CORONARY ARTERY DISEASE L. Jedlickovaa, L. Merkovskaa, J. Fedackoa, M. Janickoa, L. Jackovaa, M. Vachalcovab, M. Sajtya, T. Lopuchovskyc, B. Novakovaa, P. Jarcuskaa, D. Pellaa a 1st Department of Internal Medicine, Pavol Jozef Safarik University, Kosice, Slovakia; b Department of Cardiology, Pavol Jozef Safarik University, Kosice, Slovakia; c Department of Heart Surgery, Pavol Jozef Safarik University, Kosice, Slovakia
Objectives: Metabolic syndrome is associated with increased cardiovascular morbidity and mortality, and endothelial dysfunction is an early pathogenetic event in the metabolic syndrome. The aim of this trial was to compare the endothelial dysfunction in patients with metabolic syndrome (MS) to patients with MS and with coronary artery disease (CAD). Methods: Total of 40 patients treated with statins (20 with MS + 20 with MS and CAD) were enrolled. Using the Endo-PAT2000 device (Itamar
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Medical Ltd. Caesarea, Israel), digital pulse volume was measured in the index finger at rest for 5 minutes, then for 10 minutes after 5 minutes of occlusion with a cuff on the upper arm of the test side. Reactive hyperemia index (RHI) is calculated as the ratio between the magnitude of the averages of the post-occlusive flow mediated dilatation (FMD) and the baseline digital pulse volume corrected to systemic changes on the nonoccluded control arm. RHI decreases with dysfunction and a threshold 1000 ng/ml; Sol.eng+). Other mice reached low levels of soluble endoglin (sENG < 100 ng/ml) and were used as control mice. Western blot analysis revealed no differences in endoglin, VCAM-1, ICAM-1 and eNOS expression in aorta between Sol.eng+ mice and control mice. Conclusion: High levels of soluble endoglin did not affect markers of endothelial function/dysfunction in aorta, however further studies are required to elucidate a possible influence of soluble endoglin on the function of aortic endothelium. The study was supported by grant from The Grant Agency of Charles University in Prague number 300911/C and grant SVV/2013/267003. Transgenic mice were kindly provided by Prof. Lopez-Novoa from University of Salamanca in Spain and Dr. Bernabeu from CSIC Madrid. 13 - Endothelial cells and function EAS-0271. WEIGHT LOSS IMPROVES FASTING FLOW-MEDIATED DILATION IN ADULTS: A META-ANALYSIS OF INTERVENTION STUDIES
