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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1169.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages

Agnès Boullier; Yankun Li; Oswald Quehenberger; Wulf Palinski; Ira Tabas; Joseph L. Witztum; Yury I. Miller

From the Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego (A.B., W.P., O.Q., J.L.W. and Y.I.M.) and the Departments of Medicine, Pathology & Cell Biology, and Physiology & Cellular Biophysics, Columbia University, New York (Y.L. and I.T.).

Correspondence to Yury I. Miller, MD, PhD, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682. E-mail yumiller{at}ucsd.edu

Objective— Lipid-loaded macrophage-derived foam cells populate atherosclerotic lesions and produce many pro-inflammatory and plaque-destabilizing factors. An excessive accumulation of extensively oxidized low-density lipoprotein (OxLDL) or free cholesterol (FC), both of which are believed to be major lipid components of macrophages in advanced lesions, rapidly induces apoptosis in macrophages. Indeed, there is evidence of macrophage death in lesions, but how the surviving macrophages avoid death induced by OxLDL, FC, and other factors is not known.

Methods and Results— Minimally oxidized LDL (mmLDL), which is an early product of progressive LDL oxidation in atherosclerotic lesions, countered OxLDL-induced or FC-induced apoptosis and stimulated macrophage survival both in cell culture and in vivo. DNA fragmentation and caspase-3 activity in OxLDL-treated peritoneal macrophages were significantly reduced by coincubation with mmLDL. In a separate set of experiments, mmLDL significantly reduced annexin V binding to macrophages in which apoptosis was induced by FC loading. In both cellular models, mmLDL activated a pro-survival PI3K/Akt signaling pathway, and PI3K inhibitors, wortmannin and LY294002, eliminated the pro-survival effect of mmLDL. Immunohistochemical examination demonstrated phospho-Akt in murine atherosclerotic lesions.

Conclusions— Minimally oxidized LDL, an early form of oxidized LDL in atherosclerotic lesions, may contribute to prolonged survival of macrophage foam cells in lesions via a PI3K/Akt-dependent mechanism.

Minimally oxidized low-density lipoprotein (mmLDL) counters macrophage apoptosis induced by extensively oxidized LDL or by free cholesterol loading, both in cell culture and in vivo. The mmLDL activates a pro-survival PI3K/Akt signaling pathway, and PI3K inhibitors eliminate the pro-survival effect of mmLDL. Immunohistochemical examination demonstrates phospho-Akt in murine atherosclerotic lesions.

Key Words: apoptosis • Akt • atherosclerosis • free cholesterol • macrophage foam cell • minimally oxidized LDL • phosphoinositide 3-kinase • survival

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