This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/8/1421    most recent ATVBAHA.108.167197v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thorp, E. Articles by Tabas, I. Search for Related Content PubMed PubMed Citation Articles by Thorp, E. Articles by Tabas, I. Related Collections Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1421.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Mertk Receptor Mutation Reduces Efferocytosis Efficiency and Promotes Apoptotic Cell Accumulation and Plaque Necrosis in Atherosclerotic Lesions of Apoe^–/– Mice

Edward Thorp; Dongying Cui; Dorien M. Schrijvers; George Kuriakose; Ira Tabas

From the Departments of Medicine, Pathology & Cell Biology, and Physiology & Cellular Biophysics, Columbia University, New York.

Correspondence to Ira Tabas, MD, PhD, Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032. E-mail iat1{at}columbia.edu

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.

Methods and 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.

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.

Key Words: atherosclerosis-pathophysiology • apoptosis • phagocytosis • animal models of human disease

Related Article:

Macrophage Function and Its Impact on Atherosclerotic Lesion Composition, Progression, and Stability: The Good, the Bad, and the Ugly

Jeffrey G. Dickhout, Sana Basseri, and Richard C. Austin
Arterioscler Thromb Vasc Biol 2008 28: 1413-1415. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. Li, Y. Sun, C.-P. Liang, E. B. Thorp, S. Han, A. W. Jehle, V. Saraswathi, B. Pridgen, J. E. Kanter, R. Li, et al. Defective Phagocytosis of Apoptotic Cells by Macrophages in Atherosclerotic Lesions of ob/ob Mice and Reversal by a Fish Oil Diet Circ. Res., November 20, 2009; 105(11): 1072 - 1082. [Abstract] [Full Text] [PDF]

				E. Thorp and I. Tabas Mechanisms and consequences of efferocytosis in advanced atherosclerosis J. Leukoc. Biol., November 1, 2009; 86(5): 1089 - 1095. [Abstract] [Full Text] [PDF]

				T. Seimon and I. Tabas Mechanisms and consequences of macrophage apoptosis in atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S382 - S387. [Abstract] [Full Text] [PDF]

				M. C.H. Clarke and M. R. Bennett Cause or Consequence: What Does Macrophage Apoptosis Do in Atherosclerosis? Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 153 - 155. [Full Text] [PDF]

				D. Liao, X. Wang, M. Li, P. H. Lin, Q. Yao, and C. Chen Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages Blood, January 1, 2009; 113(1): 165 - 174. [Abstract] [Full Text] [PDF]

				J. G. Dickhout, S. Basseri, and R. C. Austin Macrophage Function and Its Impact on Atherosclerotic Lesion Composition, Progression, and Stability: The Good, the Bad, and the Ugly Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1413 - 1415. [Full Text] [PDF]