Title
Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of <tex>$Apoe^{-/-}$</tex> mice Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of <tex>$Apoe^{-/-}$</tex> mice
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Dallas, Tex. ,
Subject
Human medicine
Source (journal)
Arteriosclerosis, thrombosis, and vascular biology / American Heart Association. - Dallas, Tex., 1995, currens
Volume/pages
28(2008) :8 , p. 1421-1428
ISSN
1079-5642
1524-4636
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
AB 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 (MertkKD) have a defect in phagocytic clearance of apoptotic macrophages in vitro. Herein we test the hypothesis that the MertkKD mutation would result in increased accumulation of apoptotic cells and promote necrotic core expansion in a mouse model of advanced atherosclerosis. Methods and Results-: MertkKD;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 MertkKD;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 MertkKD lesions, consistent with defective efferocytosis. The more advanced (16-week) MertkKD;Apoe-/- plaques were more necrotic, consistent with a progression from apoptotic cell accumulation to plaque necrosis in the setting of a defective efferocytosis receptor. Conclusion-: 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.
E-info
https://repository.uantwerpen.be/docman/iruaauth/1aa094/d1bafdd6d53.pdf