on July 3, 2003
Published online before print July 3, 2003, doi: 10.1161/01.ATV.0000084825.88022.53
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Submitted on May 22, 2003
Accepted on June 19, 2003
Macrophage-Specific p53 Expression Plays a Crucial Role in Atherosclerosis Development and Plaque Remodeling
Aksam J. Merched ;
From the Departments of Medicine and Molecular & Cellular Biology and Medicine, Baylor College of Medicine, Houston, Tex.
* To whom correspondence should be addressed. E-mail: lchan{at}bcm.tmc.edu.
Objective--We first showed that absence of p53 accelerates atherosclerosis development in apoE-deficient mice. In this study, we investigated how macrophage-specific loss of p53 function might modulate atherosclerosis development in LDL receptor-deficient mice, a model for familial hypercholesterolemia.
Methods and Results--We transferred bone marrow cells isolated from p53+/+ and p53-/- mice to lethally irradiated LDL receptor-/- mice and evaluated the aortic atherosclerotic lesion areas in the recipients at different times afterward. At 15 weeks and again at 20 weeks, we found larger aortic lesion size in mice receiving p53-/- cells compared with those that received p53+/+ cells. By measuring the rate of bromodeoxyuridine incorporation, we found that the absence of p53 in macrophages stimulates cellular proliferation. In contrast, the rate of apoptosis in the atheromatous lesion was similar in the two groups of mice. Furthermore, we found that the absence of macrophage-specific p53 expression was associated with vulnerable-appearing lesions marked by increased tissue necrosis and reduced collagen deposition.
Conclusions--p53 plays a crucial role in atherosclerosis lesion development and remodeling, and macrophage-specific p53 deficiency stimulates cellular proliferation leading to a vulnerable-appearing phenotype of lesions in a mouse model of familial hypercholesterolemia.
Key words: atherosclerosis • apoptosis • proliferation • necrosis • macrophage
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