HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 10, 9440-9450, March 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/10/9440    most recent M303857200v1 Submit a Letter to Editor 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 Reilly, K. B. Articles by Hedrick, C. C. Search for Related Content PubMed PubMed Citation Articles by Reilly, K. B. Articles by Hedrick, C. C. Social Bookmarking                      What's this?

12/15-Lipoxygenase Activity Mediates Inflammatory Monocyte/Endothelial Interactions and Atherosclerosis in Vivo^*

Kelly B. Reilly, Suseela Srinivasan, Melissa E. Hatley, Mary Kim Patricia, Joanne Lannigan, David T. Bolick, George Vandenhoff, Hong Pei, Rama Natarajan¶, Jerry L. Nadler, and Catherine C. Hedrick||

From the ^¶Department of Diabetes, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010 and the Department of Microbiology and the Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia 22908

We have shown that the 12/15-lipoxygenase (12/15-LO) product 12S-hydroxyeicosatetraenoic acid increases monocyte adhesion to human endothelial cells (EC) in vitro. Recent studies have implicated 12/15-LO in mediating atherosclerosis in mice. We generated transgenic mice on a C57BL/6J (B6) background that modestly overexpressed the murine 12/15-LO gene (designated LOTG). LOTG mice had 2.5-fold elevations in levels of 12S-hydroxyeicosatetraenoic acid and a 2-fold increase in expression of 12/15-LO protein in vivo. These mice developed spontaneous aortic fatty streak lesions on a chow diet. Thus, we examined effects of 12/15-LO expression on early events leading to atherosclerosis in these mice. We found that, under basal unstimulated conditions, LOTG EC bound more monocytes than B6 control EC (18 ± 2 versus 7 ± 1 monocytes/field, respectively; p < 0.0001). Inhibition of 12/15-LO activity in LOTG EC using a 12/15-LO ribozyme completely blocked monocyte adhesion in LOTG mice. Thus, 12/15-LO activity is required for monocyte/EC adhesion in the vessel wall. Expression of ICAM-1 in aortic endothelia of LOTG mice was increased severalfold. VCAM-1 expression was not changed. In a series of blocking studies, antibodies to ₄ and ₂ integrins in WEHI monocytes blocked monocyte adhesion to both LOTG and B6 control EC. Inhibition of ICAM-1, VCAM-1, and connecting segment-1 fibronectin in EC significantly reduced adhesion of WEHI monocytes to LOTG EC. In summary, these data indicate that EC from LOTG mice are "pre-activated" to bind monocytes. Monocyte adhesion in LOTG mice is mediated through ₂ integrin and ICAM-1 interactions as well as through VLA-4 and connecting segment-1 fibronectin/VCAM-1 interactions. Thus, 12/15-LO mediates monocyte/EC interactions in the vessel wall in atherogenesis at least in part through molecular regulation of expression of endothelial adhesion molecules.

Received for publication, April 14, 2003 , and in revised form, December 10, 2003.

^* This work was supported by National Institutes of Health Grants R01 HL071141-01 (to C. C. H.), P01 HL55798-08 (to J. L. N., C. C. H., and R. N.), and DK39721 (to J. L. N.); the Iacocca Foundation (to J. L. N.); the Juvenile Diabetes Research Foundation (to J. L. N. and C. C. H.); a Pfizer Atorvastatin research award (to C. C. H.); and the American Heart Association, Mid-Atlantic Affiliate (to C. C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Cardiovascular Research Center, University of Virginia, MR5 Rm. G123, P. O. Box 801394, 415 Lane Rd., Charlottesville, VA 22908. Tel.: 434-982-4065; Fax: 434-924-2828; E-mail: cch6n{at}virginia.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Kayama, T. Minamino, H. Toko, M. Sakamoto, I. Shimizu, H. Takahashi, S. Okada, K. Tateno, J. Moriya, M. Yokoyama, et al. Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure J. Exp. Med., July 6, 2009; 206(7): 1565 - 1574. [Abstract] [Full Text] [PDF]

				M. A. Reddy, S. Sahar, L. M. Villeneuve, L. Lanting, and R. Natarajan Role of Src Tyrosine Kinase in the Atherogenic Effects of the 12/15-Lipoxygenase Pathway in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., March 1, 2009; 29(3): 387 - 393. [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]

				M. H. Nagelin, S. Srinivasan, J. Lee, J. L. Nadler, and C. C. Hedrick 12/15-Lipoxygenase Activity Increases the Degradation of Macrophage ATP-Binding Cassette Transporter G1 Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1811 - 1819. [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. McDuffie, N. A. Maybee, S. R. Keller, B. K. Stevens, J. C. Garmey, M. A. Morris, E. Kropf, C. Rival, K. Ma, J. D. Carter, et al. Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes Diabetes, January 1, 2008; 57(1): 199 - 208. [Abstract] [Full Text] [PDF]

				E. Grenier, F. S. Maupas, J.-F. Beaulieu, E. Seidman, E. Delvin, A. Sane, E. Tremblay, C. Garofalo, and E. Levy Effect of retinoic acid on cell proliferation and differentiation as well as on lipid synthesis, lipoprotein secretion, and apolipoprotein biogenesis Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1178 - G1189. [Abstract] [Full Text] [PDF]

				Y. Wen, J. Gu, S. K. Chakrabarti, K. Aylor, J. Marshall, Y. Takahashi, T. Yoshimoto, and J. L. Nadler The Role of 12/15-Lipoxygenase in the Expression of Interleukin-6 and Tumor Necrosis Factor-{alpha} in Macrophages Endocrinology, March 1, 2007; 148(3): 1313 - 1322. [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]

				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]

				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]

				J. Huber, A. Furnkranz, V. N. Bochkov, M. K. Patricia, H. Lee, C. C. Hedrick, J. A. Berliner, B. R. Binder, and N. Leitinger Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase J. Lipid Res., May 1, 2006; 47(5): 1054 - 1062. [Abstract] [Full Text] [PDF]

				M. K. Middleton, T. Rubinstein, and E. Pure Cellular and Molecular Mechanisms of the Selective Regulation of IL-12 Production by 12/15-Lipoxygenase J. Immunol., January 1, 2006; 176(1): 265 - 274. [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]

				D. T. Bolick, A. W. Orr, A. Whetzel, S. Srinivasan, M. E. Hatley, M. A. Schwartz, and C. C. Hedrick 12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-{kappa}B Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2301 - 2307. [Abstract] [Full Text] [PDF]

				A. M. Taylor, R. Hanchett, R. Natarajan, C. C. Hedrick, S. Forrest, J. L. Nadler, and C. A. McNamara The Effects of Leukocyte-Type 12/15-Lipoxygenase on Id3-Mediated Vascular Smooth Muscle Cell Growth Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2069 - 2074. [Abstract] [Full Text] [PDF]

				Y. Higashi, T. Peng, J. Du, S. Sukhanov, Y. Li, H. Itabe, S. Parthasarathy, and P. Delafontaine A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor J. Lipid Res., June 1, 2005; 46(6): 1266 - 1277. [Abstract] [Full Text] [PDF]

				C. A. Simmons, G. R. Grant, E. Manduchi, and P. F. Davies Spatial Heterogeneity of Endothelial Phenotypes Correlates With Side-Specific Vulnerability to Calcification in Normal Porcine Aortic Valves Circ. Res., April 15, 2005; 96(7): 792 - 799. [Abstract] [Full Text] [PDF]

				S. S. Rich, D. W. Bowden, S. M. Haffner, J. M. Norris, M. F. Saad, B. D. Mitchell, J. I. Rotter, C. D. Langefeld, C. C. Hedrick, L. E. Wagenknecht, et al. A Genome Scan for Fasting Insulin and Fasting Glucose Identifies a Quantitative Trait Locus on Chromosome 17p: The Insulin Resistance Atherosclerosis Study (IRAS) Family Study Diabetes, January 1, 2005; 54(1): 290 - 295. [Abstract] [Full Text] [PDF]

				P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]

				S. Srinivasan, D. T. Bolick, M. E. Hatley, R. Natarajan, K. B. Reilly, M. Yeh, C. Chrestensen, T. W. Sturgill, and C. C. Hedrick Glucose Regulates Interleukin-8 Production in Aortic Endothelial Cells through Activation of the p38 Mitogen-activated Protein Kinase Pathway in Diabetes J. Biol. Chem., July 23, 2004; 279(30): 31930 - 31936. [Abstract] [Full Text] [PDF]

				M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]