High-density lipoprotein nitration and chlorination catalyzed by myeloperoxidase impair its effect of promoting endothelial repair |
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| Institution: | 1. Division of Cardiovascular Medicine, The PERFUSE Study Group, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;2. Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey;3. Division of Cardiovascular Medicine, TIMI Study Group, Brigham and Women''s Hospital, Harvard Medical School, Boston, Massachusetts;1. Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil;2. Faculdade de Farmácia — Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Brazil;1. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria;2. Institute of Clinical Chemistry and Laboratory Medicine, General Hospital Steyr, Sierningerstraße 170, 4400 Steyr, Austria;3. Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria;4. Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria;5. Specialist Clinic for Rehabilitation Bad Gleichenberg, Schweizereiweg 4, 8344 Bad Gleichenberg, Austria;6. Department of Cardiology, Charité University Medicine Berlin, Hindenburgdamm 30, 12203 Berlin, Germany;7. Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Theodor Kutzer-Ufer 1 - 3, 68167 Mannheim, Germany;8. Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim and Augsburg, Gubenerstraße 39, 86156 Augsburg, Germany |
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| Abstract: | High-density lipoprotein (HDL) plays a key role in protecting against atherosclerosis. In cardiovascular disease, HDL can be nitrated and chlorinated by myeloperoxidase (MPO). In this study, we discovered that MPO-oxidized HDL is dysfunctional in promoting endothelial repair compared to normal HDL. Proliferation assay, wound healing, and transwell migration experiments showed that MPO-oxidized HDL was associated with a reduced stimulation of endothelial cell (EC) proliferation and migration. In addition, we found that Akt and ERK1/2 phosphorylation in ECs was significantly lower when ECs were incubated with oxidized HDL compared with normal HDL. To further determine whether oxidized HDL diminished EC migration through the PI3K/Akt and MEK/ERK pathways, we performed experiments with inhibitors of both these pathways. The transwell experiments performed in the presence of these inhibitors showed that the migration capacity was reduced and the differences observed between normal HDL and oxidized HDL were diminished. Furthermore, to study the effects of oxidized HDL on endothelial cells in vivo, we performed a carotid artery electric injury model on nude mice injected with either normal or oxidized HDL. Oxidized HDL inhibited reendothelialization compared to normal HDL in vivo. These findings implicate a key role for MPO-oxidized HDL in the pathogenesis of cardiovascular disease. |
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