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(Circulation Research. 2001;88:747.)
© 2001 American Heart Association, Inc.

Editorials

p53 and Atherosclerosis

Ira Tabas

From the Departments of Medicine and Anatomy & Cell Biology, Columbia University, New York, NY.

Correspondence to Ira Tabas, MD, PhD, Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032. E-mail iat1@columbia.edu

Key Words: p53 • atherosclerosis • macrophage • apoptosis • cellular proliferation

	Introduction

 
Subendothelial macrophages are a major cellular component of atherosclerotic lesions. In response to subendothelial retention of modified lipoproteins,^{1 2} blood-borne monocytes enter the subendothelial space, differentiate into macrophages, and accumulate large amounts of lipoprotein-derived cholesterol (foam cells).^{3 4} Specific consequences of macrophage foam-cell formation include both physical effects, such as intimal thickening, and biological effects, such as internalization of lipoproteins and secretion of biologically active molecules.^{3 5} Importantly, atherosclerosis is significantly attenuated in mice with deficient lesional macrophages attributable to dysfunctional macrophage colony–stimulating factor or decreased monocyte chemotaxis.^{6 7 8}

Remarkably, subpopulations of lesional macrophages show signs of proliferation,⁹ and other subpopulations are noted to have morphological characteristics as well as biochemical and cellular markers of apoptosis.^{10 11} Cell culture studies have shown that low levels of oxidized LDL can cause macrophages to proliferate, whereas higher levels can result in macrophage death.¹² Both cell culture and in vivo studies have also suggested that intracellular accumulation of excess unesterified cholesterol may be another important cause of lesional macrophage death.¹³ Regarding consequences of these cellular events, one might speculate that macrophage proliferation is harmful in view of the aforementioned studies with macrophage-depleted mice. Despite these mouse studies, however, there is another school of thought that suggests that macrophages may initially have a protective role by ridding the subendothelium of potentially damaging lipoproteins.^{14 15} This hypothesis would predict that macrophage proliferation could, under certain circumstances, be protective.

In terms of lesional macrophage death, safe apoptotic death (ie, cellular condensation followed by the phagocytosis and disposal of apoptotic bodies) may simply . . . [Full Text of this Article]

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