Reversal of Hypoxia in Murine Atherosclerosis Prevents Necrotic Core Expansion by Enhancing Efferocytosis

Author:

Marsch Elke1,Theelen Thomas L.1,Demandt Jasper A.F.1,Jeurissen Mike1,van Gink Mathijs1,Verjans Robin1,Janssen Anique1,Cleutjens Jack P.1,Meex Steven J.R.1,Donners Marjo M.1,Haenen Guido R.1,Schalkwijk Casper G.1,Dubois Ludwig J.1,Lambin Philippe1,Mallat Ziad1,Gijbels Marion J.1,Heemskerk Johan W.M.1,Fisher Edward A.1,Biessen Erik A.L.1,Janssen Ben J.1,Daemen Mat J.A.P.1,Sluimer Judith C.1

Affiliation:

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,...

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% O 2 , 5% CO 2 ) 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 pO 2 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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