Elke Marsch1, Thomas L Theelen1, Jasper A F Demandt1, Mike Jeurissen1, Mathijs van Gink1, Robin Verjans1, Anique Janssen1, Jack P Cleutjens1, Steven J R Meex1, Marjo M Donners1, Guido R Haenen1, Casper G Schalkwijk1, Ludwig J Dubois1, Philippe Lambin1, Ziad Mallat1, Marion J Gijbels1, Johan W M Heemskerk1, Edward A Fisher1, Erik A L Biessen1, Ben J Janssen1, Mat J A P Daemen1, Judith C Sluimer2. 1. From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM) (E.M., T.L.T., J.A.F.D., M.J., M.v.G., R.V., A.J., J.P.C., M.M.D., M.J.G., E.A.L.B., J.C.S.), Department of Clinical Chemistry (S.J.R.M.), Department of Toxicology (G.R.H.), Department of Internal Medicine, CARIM (C.G.S.), Department of Radiation Oncology (Maastro Lab), GROW (L.J.D., P.L.), Department of Molecular Genetics, CARIM (M.J.G.), Department of Biochemistry, CARIM (J.W.M.H.), Department of Pharmacology, CARIM (B.J.J.), Maastricht University Medical Centre, Maastricht, The Netherlands; Paris Centre de Recherche Cardiovasculaire (PARCC) Inserm-UMR 970, Paris, France (Z.M.); Department of Medicine, University of Cambridge, Cambridge, United Kingdom (Z.M.); Department of Medical Biochemistry (M.J.G.) and Department of Pathology (M.J.A.P.D.), AMC, Amsterdam, The Netherlands; and Department of Medicine (Cardiology), New York University School of Medicine, New York (E.A.F.). 2. From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM) (E.M., T.L.T., J.A.F.D., M.J., M.v.G., R.V., A.J., J.P.C., M.M.D., M.J.G., E.A.L.B., J.C.S.), Department of Clinical Chemistry (S.J.R.M.), Department of Toxicology (G.R.H.), Department of Internal Medicine, CARIM (C.G.S.), Department of Radiation Oncology (Maastro Lab), GROW (L.J.D., P.L.), Department of Molecular Genetics, CARIM (M.J.G.), Department of Biochemistry, CARIM (J.W.M.H.), Department of Pharmacology, CARIM (B.J.J.), Maastricht University Medical Centre, Maastricht, The Netherlands; Paris Centre de Recherche Cardiovasculaire (PARCC) Inserm-UMR 970, Paris, France (Z.M.); Department of Medicine, University of Cambridge, Cambridge, United Kingdom (Z.M.); Department of Medical Biochemistry (M.J.G.) and Department of Pathology (M.J.A.P.D.), AMC, Amsterdam, The Netherlands; and Department of Medicine (Cardiology), New York University School of Medicine, New York (E.A.F.). judith.sluimer@maastrichtuniversity.nl.
Abstract
OBJECTIVE: Advanced murine and human plaques are hypoxic, but it remains unclear whether plaque hypoxia is causally related to atherogenesis. Here, we test the hypothesis that reversal of hypoxia in atherosclerotic plaques by breathing hyperoxic carbogen gas will prevent atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) were fed a Western-type diet, exposed to carbogen (95% O2, 5% CO2) or air, and the effect on plaque hypoxia, size, and phenotype was studied. First, the hypoxic marker pimonidazole was detected in murine LDLR(-/-) plaque macrophages from plaque initiation onwards. Second, the efficacy of breathing carbogen (90 minutes, single exposure) was studied. Compared with air, carbogen increased arterial blood pO2 5-fold in LDLR(-/-) mice and reduced plaque hypoxia in advanced plaques of the aortic root (-32%) and arch (-84%). Finally, the effect of repeated carbogen exposure on progression of atherosclerosis was studied in LDLR(-/-) mice fed a Western-type diet for an initial 4 weeks, followed by 4 weeks of diet and carbogen or air (both 90 min/d). Carbogen reduced plaque hypoxia (-40%), necrotic core size (-37%), and TUNEL(+) (terminal uridine nick-end labeling positive) apoptotic cell content (-50%) and increased efferocytosis of apoptotic cells by cluster of differentiation 107b(+) (CD107b, MAC3) macrophages (+36%) in advanced plaques of the aortic root. Plaque size, plasma cholesterol, hematopoiesis, and systemic inflammation were unchanged. In vitro, hypoxia hampered efferocytosis by bone marrow-derived macrophages, which was dependent on the receptor Mer tyrosine kinase. CONCLUSIONS: Carbogen restored murine plaque oxygenation and prevented necrotic core expansion by enhancing efferocytosis, likely via Mer tyrosine kinase. Thus, plaque hypoxia is causally related to necrotic core expansion.
OBJECTIVE: Advanced murine and human plaques are hypoxic, but it remains unclear whether plaque hypoxia is causally related to atherogenesis. Here, we test the hypothesis that reversal of hypoxia in atherosclerotic plaques by breathing hyperoxic carbogen gas will prevent atherosclerosis. APPROACH AND RESULTS:Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) were fed a Western-type diet, exposed to carbogen (95% O2, 5% CO2) or air, and the effect on plaque hypoxia, size, and phenotype was studied. First, the hypoxic marker pimonidazole was detected in murineLDLR(-/-) plaque macrophages from plaque initiation onwards. Second, the efficacy of breathing carbogen (90 minutes, single exposure) was studied. Compared with air, carbogen increased arterial blood pO2 5-fold in LDLR(-/-) mice and reduced plaque hypoxia in advanced plaques of the aortic root (-32%) and arch (-84%). Finally, the effect of repeated carbogen exposure on progression of atherosclerosis was studied in LDLR(-/-) mice fed a Western-type diet for an initial 4 weeks, followed by 4 weeks of diet and carbogen or air (both 90 min/d). Carbogen reduced plaque hypoxia (-40%), necrotic core size (-37%), and TUNEL(+) (terminal uridine nick-end labeling positive) apoptotic cell content (-50%) and increased efferocytosis of apoptotic cells by cluster of differentiation 107b(+) (CD107b, MAC3) macrophages (+36%) in advanced plaques of the aortic root. Plaque size, plasma cholesterol, hematopoiesis, and systemic inflammation were unchanged. In vitro, hypoxia hampered efferocytosis by bone marrow-derived macrophages, which was dependent on the receptor Mer tyrosine kinase. CONCLUSIONS:Carbogen restored murine plaque oxygenation and prevented necrotic core expansion by enhancing efferocytosis, likely via Mer tyrosine kinase. Thus, plaque hypoxia is causally related to necrotic core expansion.
Authors: Shirley Dehn; Matthew DeBerge; Xin-Yi Yeap; Laurent Yvan-Charvet; Deyu Fang; Holger K Eltzschig; Stephen D Miller; Edward B Thorp Journal: J Immunol Date: 2016-09-26 Impact factor: 5.422
Authors: Sweena M Chaudhari; Judith C Sluimer; Miriam Koch; Thomas L Theelen; Helga D Manthey; Martin Busch; Celia Caballero-Franco; Frederick Vogel; Clément Cochain; Jaroslav Pelisek; Mat J Daemen; Manfred B Lutz; Agnes Görlach; Stephan Kissler; Heike M Hermanns; Alma Zernecke Journal: Arterioscler Thromb Vasc Biol Date: 2015-09-24 Impact factor: 8.311
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