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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1198.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Increased Cholesterol Deposition, Expression of Scavenger Receptors, and Response to Chemotactic Factors in Abca1-Deficient Macrophages

Omar L. Francone; Lori Royer; Germaine Boucher; Mehrdad Haghpassand; Ann Freeman; Dominique Brees; Robert J. Aiello

From Pfizer Global Research and Development, Groton, Conn.

Correspondence to Omar L. Francone, Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Eastern Point Rd, Groton, CT 06340. E-mail omar.l.francone{at}pfizer.com

Objective— Studies in bone marrow transplanted from ATP-binding cassette transporter A1 (ABCA1)–deficient mice into normal mice provides direct evidence that the absence of leukocyte ABCA1 exerts a marked proatherogenic effect independent of changes in plasma lipids, suggesting that ABCA1 plays a key role in the regulation of cholesterol homeostasis and function of macrophages. Therefore, we examined whether the absence of ABCA1 affects the morphology, properties, and functional activities of macrophages that could be related to the development of atherosclerosis.

Methods and Results— We conducted a series of experiments in macrophages isolated from Abca1-deficient and wild-type mice and compared several of their properties that are thought to be related to the development of atherosclerosis. Macrophages isolated from Abca1-deficient mice have an increase in cholesterol content, expression of scavenger receptors, and secretion of chemokines, growth factors, and cytokines, resulting in an increased ability to respond to a variety of chemotactic factors.

Conclusion— Our studies indicate that the absence of ABCA1 leads to significant changes in the morphology, properties, and functional activities of macrophages. These changes, together with the proinflammatory condition present in ABCA1-deficient mice and increased reactivity of macrophages to chemotactic factors, play a key role in the development and progression of atherosclerosis.

The ABCA1 role in macrophage morphology, properties, and functional activities was examined in wild-type and Abca1-deficient mice. Our studies demonstrate that the absence of ABCA1 leads to an inflammatory activation of macrophages, accompanied by cholesterol loading, increased expression of scavenger receptors, and synthesis of chemokines, cytokines, and growth factors, resulting in an increased ability of macrophages to respond to a variety of chemotactic factors.

Key Words: ABCA1 • cholesterol homeostasis • scavenger receptors • inflammation • atherosclerosis

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