Published Online
on April 21, 2003

A more recent version of this article appeared on June 1, 2003

This Article Full Text (PDF) All Versions of this Article: 41/6/1294    most recent 01.HYP.0000069011.18333.08v1 Alert me when this article is cited Alert me if a correction is posted 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 Reddy, M. A. Articles by Natarajan, R. Search for Related Content PubMed PubMed Citation Articles by Reddy, M. A. Articles by Natarajan, R.

Submitted on January 30, 2003
Revised on February 28, 2003

Reduced Growth Factor Responses in Vascular Smooth Muscle Cells Derived from 12/15-Lipoxygenase-Deficient Mice

Marpadga A. Reddy; Young-Sook Kim; Linda Lanting; and Rama Natarajan^*

From the Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, Calif.

^* To whom correspondence should be addressed. E-mail: rnatarajan{at}coh.org.

Abstract--Biochemical and genetic evidence support the involvement of leukocyte-type 12/15-lipoxygenase enzyme and its products in the atherogenic process. We recently showed that products of the 12/15-lipoxygenase pathway play an important role in mediating hypertrophy, matrix protein production, and inflammatory gene expression in vascular smooth muscle cells (VSMC) through activation of mitogen activated protein kinases and key transcription factors. The current study is aimed at establishing the in vivo role of 12/15-lipoxygenase in VSMC by comparing growth factor-induced responses in VSMC derived from 12/15-lipoxygenase knockout mice versus genetic control wild-type mice. In the lipoxygenase knockout cells, 12/15-lipoxygenase protein was not expressed, and levels of its product, 12(S)-hydroxyeicosatetraenoic acid, were reduced (51% of wild type). Knockout cells exhibited significantly lower rates of growth factor-induced migration, fibronectin production, and incorporation of ³H-thymidine and ³H-leucine (54%, 55%, 61%, and 57% of wild type, respectively). Growth factor-induced superoxide production and p38 mitogen-activated protein kinase activation were also reduced in knockout cells. Serum-stimulated AP-1 transcription factor activation was markedly reduced (50% of wild type), whereas cAMP response element binding protein activation was abrogated in knockout cells. Furthermore, growth factor-induced mRNA expression of immediate early genes and fibronectin were also greatly reduced. These results suggest that the modulation of specific signaling pathways and growth-responsive genes may be responsible for the altered growth factor responses in the lipoxygenase knockout cells. They also demonstrate the important in vivo role of vascular 12/15-lipoxygenase in VSMC growth, migration, and matrix responses associated with hypertension, atherosclerosis, and restenosis.

Key words: lipoxygenase • muscle, smooth, vascular • signal transduction • angiotensin II • platelet-derived growth factor • gene regulation

This article has been cited by other articles:

				M. K. Middleton, A. M. Zukas, T. Rubinstein, M. Kinder, E. H. Wilson, P. Zhu, I. A. Blair, C. A. Hunter, and E. Pure 12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis Infect. Immun., December 1, 2009; 77(12): 5690 - 5700. [Abstract] [Full Text] [PDF]

				M. Terashima, Y. Ohashi, H. Azumi, K. Otsui, H. Kaneda, K. Awano, S. Kobayashi, T. Honjo, T. Suzuki, K. Maeda, et al. Impact of NAD(P)H Oxidase-Derived Reactive Oxygen Species on Coronary Arterial Remodeling: A Comparative Intravascular Ultrasound and Histochemical Analysis of Atherosclerotic Lesions Circ Cardiovasc Interv, June 1, 2009; 2(3): 196 - 204. [Abstract] [Full Text] [PDF]

				T. Zhao, D. Wang, S. Y. Cheranov, M. Karpurapu, K. R. Chava, V. Kundumani-Sridharan, D. A. Johnson, J. S. Penn, and G. N. Rao A novel role for activating transcription factor-2 in 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis J. Lipid Res., March 1, 2009; 50(3): 521 - 533. [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]

				R. Siekmeier, T. Grammer, and W. Marz Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 279 - 297. [Abstract] [PDF]

				Z.-G. Xu, H. Yuan, L. Lanting, S.-L. Li, M. Wang, N. Shanmugam, M. Kato, S. G. Adler, M. A. Reddy, and R. Natarajan Products of 12/15-Lipoxygenase Upregulate the Angiotensin II Receptor J. Am. Soc. Nephrol., March 1, 2008; 19(3): 559 - 569. [Abstract] [Full Text] [PDF]

				F. A. Yaghini, F. Li, and K. U. Malik Expression and Mechanism of Spleen Tyrosine Kinase Activation by Angiotensin II and Its Implication in Protein Synthesis in Rat Vascular Smooth Muscle Cells J. Biol. Chem., June 8, 2007; 282(23): 16878 - 16890. [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]

				M. A. Reddy, S.-L. Li, S. Sahar, Y.-S. Kim, Z.-G. Xu, L. Lanting, and R. Natarajan Key Role of Src Kinase in S100B-induced Activation of the Receptor for Advanced Glycation End Products in Vascular Smooth Muscle Cells J. Biol. Chem., May 12, 2006; 281(19): 13685 - 13693. [Abstract] [Full Text] [PDF]

				I. R. Preston, N. S. Hill, R. R. Warburton, and B. L. Fanburg Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L367 - L374. [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]

				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]

				S.-L. Li, R. S. Dwarakanath, Q. Cai, L. Lanting, and R. Natarajan Effects of silencing leukocyte-type 12/15-lipoxygenase using short interfering RNAs J. Lipid Res., February 1, 2005; 46(2): 220 - 229. [Abstract] [Full Text] [PDF]

				N. R. Madamanchi, A. Vendrov, and M. S. Runge Oxidative Stress and Vascular Disease Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 29 - 38. [Abstract] [Full Text] [PDF]

				R. Natarajan and J. L. Nadler Lipid Inflammatory Mediators in Diabetic Vascular Disease Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1542 - 1548. [Abstract] [Full Text] [PDF]

				Q. Cai, L. Lanting, and R. Natarajan Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis Am J Physiol Cell Physiol, September 1, 2004; 287(3): C707 - C714. [Abstract] [Full Text] [PDF]