This Article Full Text Full Text (PDF) Correction (v110,p3156) All Versions of this Article: 110/14/2024    most recent 01.CIR.0000143628.37680.F6v1 Alert me when this article is cited 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 Huo, Y. Articles by Ley, K. Search for Related Content PubMed PubMed Citation Articles by Huo, Y. Articles by Ley, K. Related Collections Animal models of human disease Pathophysiology Risk Factors Mechanism of atherosclerosis/growth factors Other Vascular biology

(Circulation. 2004;110:2024-2031.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

Yuqing Huo, MD, PhD^*; Lei Zhao, MD^*; Matthew Craig Hyman, BS; Pavel Shashkin, PhD; Brian L. Harry, BS; Tracy Burcin, MS; S. Bradley Forlow, PhD; Matthew A. Stark, BS; David F. Smith, MS; Sean Clarke, BS; Suseela Srinivasan, PhD; Catherine C. Hedrick, PhD; Domenico Praticò, MD; Joseph L. Witztum, MD; Jerry L. Nadler, MD; Colin D. Funk, PhD; Klaus Ley, MD

From the University of Virginia (Y.H., M.C.H., P.S., B.L.H., T.B., S.B.F., M.A.S., D.F.S., S.C., S.S., C.C.H., J.L.N., K.L.), Charlottesville, Va; University of Pennsylvania (L.Z., D.P., C.D.F.), Philadelphia, Pa; and University of California (J.L.W), San Diego, Calif.

Correspondence to Yuqing Huo, MD, PhD, Cardiovascular Division and Vascular Biology Center, University of Minnesota, MMC 508, 420 Delaware St SE, Minneapolis, MN 55455. E-mail Yuqing{at}umn.edu

Received May 23, 2004; revision received July 10, 2004; accepted July 21, 2004.

Background— Mice lacking leukocyte type 12/15-lipoxygenase (12/15-LO) show reduced atherosclerosis in several models. 12/15-LO is expressed in a variety of cells, including vascular cells, adipocytes, macrophages, and cardiomyocytes. The purpose of this study was to determine which cellular source of 12/15-LO is important for atherosclerosis.

Methods and Results— Bone marrow from 12/15-LO^–/–/apoE^–/– mice was transplanted into apoE^–/– mice and vice versa. Deficiency of 12/15-LO in bone marrow cells protected apoE^–/– mice fed a Western diet from atherosclerosis to the same extent as complete absence of 12/15-LO, although plasma 8,12-iso-iPF₂-IV, a measure of lipid peroxidation, remained elevated. 12/15-LO^–/–/apoE^–/– mice regained the severity of atherosclerotic lesion typical of apoE^–/– mice after replacement of their bone marrow cells with bone marrow from apoE^–/– mice. Peritoneal macrophages obtained from wild-type but not 12/15-LO^–/– mice caused endothelial activation in the presence of native LDL. Absence of 12/15-LO decreased the ability of macrophages to form foam cells when exposed to LDL.

Conclusions— We conclude that macrophage 12/15-LO plays a dominant role in the development of atherosclerosis by promoting endothelial inflammation and foam cell formation.

Key Words: atherosclerosis • cell adhesion molecules • endothelium • lipids

This article has been cited by other articles:

				M. H. Nagelin, S. Srinivasan, J. L. Nadler, and C. C. Hedrick Murine 12/15-Lipoxygenase Regulates ATP-binding Cassette Transporter G1 Protein Degradation through p38- and JNK2-dependent Pathways J. Biol. Chem., November 6, 2009; 284(45): 31303 - 31314. [Abstract] [Full Text] [PDF]

				M. Almeida, E. Ambrogini, L. Han, S. C. Manolagas, and R. L. Jilka Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-{gamma} Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton J. Biol. Chem., October 2, 2009; 284(40): 27438 - 27448. [Abstract] [Full Text] [PDF]

				A. Zarbock, M. R. DiStasi, E. Smith, J. M. Sanders, G. Kronke, B. L. Harry, S. von Vietinghoff, K. Buscher, J. L. Nadler, and K. Ley Improved Survival and Reduced Vascular Permeability by Eliminating or Blocking 12/15-Lipoxygenase in Mouse Models of Acute Lung Injury (ALI) J. Immunol., October 1, 2009; 183(7): 4715 - 4722. [Abstract] [Full Text] [PDF]

				C. Wei, P. Zhu, S. J. Shah, and I. A. Blair 15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation Mol. Pharmacol., September 1, 2009; 76(3): 516 - 525. [Abstract] [Full Text] [PDF]

				G. Kronke, J. Katzenbeisser, S. Uderhardt, M. M. Zaiss, C. Scholtysek, G. Schabbauer, A. Zarbock, M. I. Koenders, R. Axmann, J. Zwerina, et al. 12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis J. Immunol., September 1, 2009; 183(5): 3383 - 3389. [Abstract] [Full Text] [PDF]

				D. Poeckel, K. A. Zemski Berry, R. C. Murphy, and C. D. Funk Dual 12/15- and 5-Lipoxygenase Deficiency in Macrophages Alters Arachidonic Acid Metabolism and Attenuates Peritonitis and Atherosclerosis in ApoE Knock-out Mice J. Biol. Chem., July 31, 2009; 284(31): 21077 - 21089. [Abstract] [Full Text] [PDF]

				H. Wang, W. Zhang, C. Zhu, C. Bucher, B. R. Blazar, C. Zhang, J.-F. Chen, J. Linden, C. Wu, and Y. Huo Inactivation of the Adenosine A2A Receptor Protects Apolipoprotein E-Deficient Mice From Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1046 - 1052. [Abstract] [Full Text] [PDF]

				S.-H. Choi, R. Harkewicz, J. H. Lee, A. Boullier, F. Almazan, A. C. Li, J. L. Witztum, Y. S. Bae, and Y. I. Miller Lipoprotein Accumulation in Macrophages via Toll-Like Receptor-4-Dependent Fluid Phase Uptake Circ. Res., June 19, 2009; 104(12): 1355 - 1363. [Abstract] [Full Text] [PDF]

				K. R. Chava, M. Karpurapu, D. Wang, M. Bhanoori, V. Kundumani-Sridharan, Q. Zhang, T. Ichiki, W. C. Glasgow, and G. N. Rao CREB-Mediated IL-6 Expression Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-Induced Vascular Smooth Muscle Cell Migration Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 809 - 815. [Abstract] [Full Text] [PDF]

				D. Steinberg The LDL modification hypothesis of atherogenesis: an update J. Lipid Res., April 1, 2009; 50(Supplement): S376 - S381. [Abstract] [Full Text] [PDF]

				V. Dioszeghy, M. Rosas, B. H. Maskrey, C. Colmont, N. Topley, P. Chaitidis, H. Kuhn, S. A. Jones, P. R. Taylor, and V. B. O'Donnell 12/15-Lipoxygenase Regulates the Inflammatory Response to Bacterial Products In Vivo J. Immunol., November 1, 2008; 181(9): 6514 - 6524. [Abstract] [Full Text] [PDF]

				C. S. Nunemaker, M. Chen, H. Pei, S. D. Kimble, S. R. Keller, J. D. Carter, Z. Yang, K. M. Smith, R. Wu, M. H. Bevard, et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by western diet Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1065 - E1075. [Abstract] [Full Text] [PDF]

				A. J. Merched, K. Ko, K. H. Gotlinger, C. N. Serhan, and L. Chan Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators FASEB J, October 1, 2008; 22(10): 3595 - 3606. [Abstract] [Full Text] [PDF]

				I. A. Butovich and S. M. Lukyanova Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies J. Lipid Res., June 1, 2008; 49(6): 1284 - 1294. [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]

				Y. Wen, J. Gu, G. E. Vandenhoff, X. Liu, and J. L. Nadler Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1933 - H1938. [Abstract] [Full Text] [PDF]

				M. K. Middleton, A. M. Zukas, T. Rubinstein, M. Jacob, P. Zhu, L. Zhao, I. Blair, and E. Pure Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease J. Exp. Med., October 30, 2006; 203(11): 2529 - 2540. [Abstract] [Full Text] [PDF]

				S.-l. Li, M. A. Reddy, Q. Cai, L. Meng, H. Yuan, L. Lanting, and R. Natarajan Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice Diabetes, September 1, 2006; 55(9): 2611 - 2619. [Abstract] [Full Text] [PDF]

				S. Sukhanov, Y. Higashi, S.-Y. Shai, H. Itabe, K. Ono, S. Parthasarathy, and P. Delafontaine Novel Effect of Oxidized Low-Density Lipoprotein: Cellular ATP Depletion via Downregulation of Glyceraldehyde-3-Phosphate Dehydrogenase Circ. Res., July 21, 2006; 99(2): 191 - 200. [Abstract] [Full Text] [PDF]

				J. Sainz and M. Sata Maintenance of Vascular Homeostasis by Bone Marrow-Derived Cells. Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1196 - 1197. [Full Text] [PDF]

				C. D. Funk Lipoxygenase Pathways as Mediators of Early Inflammatory Events in Atherosclerosis. Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1204 - 1206. [Full Text] [PDF]

				S. Saika, K. Ikeda, O. Yamanaka, K. C. Flanders, Y. Okada, T. Miyamoto, A. Kitano, A. Ooshima, Y. Nakajima, Y. Ohnishi, et al. Loss of Tumor Necrosis Factor {alpha} Potentiates Transforming Growth Factor {beta}-mediated Pathogenic Tissue Response during Wound Healing Am. J. Pathol., June 1, 2006; 168(6): 1848 - 1860. [Abstract] [Full Text] [PDF]

				D. T. Bolick, S. Srinivasan, A. Whetzel, L. C. Fuller, and C. C. Hedrick 12/15 Lipoxygenase Mediates Monocyte Adhesion to Aortic Endothelium in Apolipoprotein E-Deficient Mice Through Activation of RhoA and NF-{kappa}B Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1260 - 1266. [Abstract] [Full Text] [PDF]

				A. Boullier, Y. Li, O. Quehenberger, W. Palinski, I. Tabas, J. L. Witztum, and Y. I. Miller Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1169 - 1176. [Abstract] [Full Text] [PDF]

				H. Pei, J. Gu, P.-R. Thimmalapura, A. Mison, and J. L. Nadler Activation of the 12-lipoxygenase and signal transducer and activator of transcription pathway during neointima formation in a model of the metabolic syndrome Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E92 - E102. [Abstract] [Full Text] [PDF]

				G. Li, J. M. Sanders, E. T. Phan, K. Ley, and I. J. Sarembock Arterial Macrophages and Regenerating Endothelial Cells Express P-Selectin in Atherosclerosis-Prone Apolipoprotein E-Deficient Mice Am. J. Pathol., December 1, 2005; 167(6): 1511 - 1518. [Abstract] [Full Text] [PDF]

				B. Zhang, H. Cao, and G. N. Rao 15(S)-Hydroxyeicosatetraenoic Acid Induces Angiogenesis via Activation of PI3K-Akt-mTOR-S6K1 Signaling Cancer Res., August 15, 2005; 65(16): 7283 - 7291. [Abstract] [Full Text] [PDF]

				K. Choy, K. Beck, F. Y. Png, B. J. Wu, S. B. Leichtweis, S. R. Thomas, J. Y. Hou, K. D. Croft, T. A. Mori, and R. Stocker Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1684 - 1690. [Abstract] [Full Text] [PDF]

				Y. I. Miller, S. Viriyakosol, D. S. Worrall, A. Boullier, S. Butler, and J. L. Witztum Toll-Like Receptor 4-Dependent and -Independent Cytokine Secretion Induced by Minimally Oxidized Low-Density Lipoprotein in Macrophages Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1213 - 1219. [Abstract] [Full Text] [PDF]