This Article Full Text Full Text (PDF) All Versions of this Article: 26/5/1169    most recent 01.ATV.0000210279.97308.9av1 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 Boullier, A. Articles by Miller, Y. I. Search for Related Content PubMed PubMed Citation Articles by Boullier, A. Articles by Miller, Y. I.

(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

This article has been cited by other articles:

				D. Namgaladze, C. Jennewein, S. Preiss, A. von Knethen, and B. Brune Attenuated suppression of the oxidative burst by cells dying in the presence of oxidized low density lipoprotein J. Lipid Res., November 1, 2009; 50(11): 2173 - 2181. [Abstract] [Full Text] [PDF]

				Y. S. Bae, J. H. Lee, S. H. Choi, S. Kim, F. Almazan, J. L. Witztum, and Y. I. Miller Macrophages Generate Reactive Oxygen Species in Response to Minimally Oxidized Low-Density Lipoprotein: Toll-Like Receptor 4- and Spleen Tyrosine Kinase-Dependent Activation of NADPH Oxidase 2 Circ. Res., January 30, 2009; 104(2): 210 - 218. [Abstract] [Full Text] [PDF]

				N. E. Freeman-Anderson, T. G. Pickle, C. D. Netherland, A. Bales, N. E. Buckley, and D. P. Thewke Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis J. Lipid Res., November 1, 2008; 49(11): 2338 - 2346. [Abstract] [Full Text] [PDF]

				R. Harkewicz, K. Hartvigsen, F. Almazan, E. A. Dennis, J. L. Witztum, and Y. I. Miller Cholesteryl Ester Hydroperoxides Are Biologically Active Components of Minimally Oxidized Low Density Lipoprotein J. Biol. Chem., April 18, 2008; 283(16): 10241 - 10251. [Abstract] [Full Text] [PDF]

				D. Namgaladze, A. Kollas, and B. Brune Oxidized LDL attenuates apoptosis in monocytic cells by activating ERK signaling J. Lipid Res., January 1, 2008; 49(1): 58 - 65. [Abstract] [Full Text] [PDF]

				A. Neekhra, S. Luthra, M. Chwa, G. Seigel, A. L. Gramajo, B. D. Kuppermann, and M. C. Kenney Caspase-8, -12, and -3 Activation by 7-Ketocholesterol in Retinal Neurosensory Cells Invest. Ophthalmol. Vis. Sci., March 1, 2007; 48(3): 1362 - 1367. [Abstract] [Full Text] [PDF]

				Y. Li and I. Tabas The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis J. Leukoc. Biol., February 1, 2007; 81(2): 483 - 491. [Abstract] [Full Text] [PDF]

				D. Namgaladze and B. Brune Phospholipase A2-Modified Low-Density Lipoprotein Activates the Phosphatidylinositol 3-Kinase-Akt Pathway and Increases Cell Survival in Monocytic Cells Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2510 - 2516. [Abstract] [Full Text] [PDF]