Reversal of hypoxia in murine atherosclerosis prevents necrotic core expansion by enhancing efferocytosis.

Autor:	Marsch E; 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.)., Theelen TL; 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.)., Demandt JA; 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.)., Jeurissen M; 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.)., van Gink M; 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.)., Verjans R; 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.)., Janssen A; 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.)., Cleutjens JP; 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.)., Meex SJ; 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.)., Donners MM; 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.)., Haenen GR; 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.)., Schalkwijk CG; 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.)., Dubois LJ; 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.)., Lambin P; 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.)., Mallat Z; 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.)., Gijbels MJ; 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.)., Heemskerk JW; 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.)., Fisher EA; 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.)., Biessen EA; 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.)., Janssen BJ; 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.)., Daemen MJ; 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.)., Sluimer JC; 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.
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2014 Dec; Vol. 34 (12), pp. 2545-53. Date of Electronic Publication: 2014 Sep 25.
DOI:	10.1161/ATVBAHA.114.304023
Abstrakt:	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. (© 2014 American Heart Association, Inc.)
Databáze:	MEDLINE
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