title: Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice.
abstract: OBJECTIVE
  Atherosclerotic plaques that are prone to disruption and acute thrombotic vascular events are characterized by large necrotic cores. Necrotic cores result from the combination of macrophage apoptosis and defective phagocytic clearance (efferocytosis) of these apoptotic cells. We previously showed that macrophages with tyrosine kinase-defective Mertk receptor (Mertk(KD)) have a defect in phagocytic clearance of apoptotic macrophages in vitro. Herein we test the hypothesis that the Mertk(KD) mutation would result in increased accumulation of apoptotic cells and promote necrotic core expansion in a mouse model of advanced atherosclerosis.
  
  
  RESULTS
  Mertk(KD);Apoe(-/-) mice and control Apoe(-/-) mice were fed a Western-type diet for 10 or 16 weeks, and aortic root lesions were analyzed for apoptosis and plaque necrosis. We found that the plaques of the Mertk(KD);Apoe(-/-) mice had a significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells. Most importantly, there were more non-macrophage-associated apoptotic cells in the Mertk(KD) lesions, consistent with defective efferocytosis. The more advanced (16-week) Mertk(KD);Apoe(-/-) plaques were more necrotic, consistent with a progression from apoptotic cell accumulation to plaque necrosis in the setting of a defective efferocytosis receptor.
  
  
  CONCLUSIONS
  In a mouse model of advanced atherosclerosis, mutation of the phagocytic Mertk receptor promotes the accumulation of apoptotic cells and the formation of necrotic plaques. These data are consistent with the notion that a defect in an efferocytosis receptor can accelerate the progression of atherosclerosis and suggest a novel therapeutic target to prevent advanced plaque progression and its clinical consequences.
authors.affiliation: Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Thorp
authors.forename: Dongying
authors.initials: D
authors.lastname: Cui
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
authors.forename: George
authors.initials: G
authors.lastname: Kuriakose
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000503:physiopathology*; D004195:Disease Models, Animal; D005487:Foam Cells / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010587:Phagocytosis / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D001057:Apolipoproteins E; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase