on October 24, 2002
Published online before print October 24, 2002, doi: 10.1161/01.ATV.0000043453.21629.3B
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 21, 2002
Accepted on September 30, 2002
Oxidized LDL-Induced Smooth Muscle Cell Proliferation Involves the EGF Receptor/PI-3 Kinase/Akt and the Sphingolipid Signaling Pathways
Nathalie Auge ;
From INSERM U-466, Université Paul Sabatier, Toulouse, France.
* To whom correspondence should be addressed. E-mail: anesalv{at}toulouse.inserm.fr.
Objective—Oxidized low-density lipoprotein (oxLDL)-induced smooth muscle cell (SMC) proliferation requires the coactivation of various signaling pathways, namely sphingomyelin/ceramide/sphingosine-1-phosphate, epithelial growth factor receptor (EGFR), and phosphoinositide 3-kinase (PI-3K) pathways. This study aimed to clarify the respective role and the hypothetical cross-talk between sphingomyelin/ceramide/sphingosine-1-phosphate, EGFR, and PI-3K/Akt pathways in the balance between mitogenic and cytotoxic effects elicited by oxLDL.
Methods and Results—Coimmunoprecipitation experiments and the use of inhibitors and dominant-negative mutant showed that oxLDL-induced PI-3K activation is dependent on EGFR. PI-3K activation is independent of the sphingomyelin/ceramide/sphingosine-1-phosphate pathway, because PI-3K inhibition by LY294002 or dominant-negative 
p85 mutant does not abrogate sphingomyelin hydrolysis, and, conversely, the use of permeant C2-ceramide and of N,N-dimethyl-sphingosine, a sphingosine kinase inhibitor, does not alter PI-3K activity. Activation of Akt/PKB by oxLDL requires PI-3K, as shown by the inhibition by LY204002 and in p85 SMC. The inhibition of Akt/PKB by PI-3K inhibitor LY204002 or by overexpression of kinase-dead Akt shifted the mitogenic effect of oxLDL toward apoptosis, thus suggesting that the PI-3K/Akt pathway acts as a survival pathway.
Conclusions—SMC proliferation elicited by moderate concentrations of oxLDL involves the sphingomyelin/ceramide/sphingosine-1-phosphate pathway, which leads to extracellular regulated kinase 1/2 activation and DNA synthesis, and the EGFR/PI-3K/Akt pathway, which prevents the apoptotic effect of oxLDL.
Key words: proliferation • survival • oxidized low-density lipoprotein • phosphoinositide 3-kinase • epithelial growth factor receptor • ceramide
This article has been cited by other articles:
 |
|
 |
|
  C. Pavoine and F. Pecker Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology Cardiovasc Res, May 1, 2009; 82(2): 175 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sanson, N. Auge, C. Vindis, C. Muller, Y. Bando, J.-C. Thiers, M.-A. Marachet, K. Zarkovic, Y. Sawa, R. Salvayre, et al. Oxidized Low-Density Lipoproteins Trigger Endoplasmic Reticulum Stress in Vascular Cells: Prevention by Oxygen-Regulated Protein 150 Expression Circ. Res., February 13, 2009; 104(3): 328 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashi, S. Sukhanov, S. Parthasarathy, and P. Delafontaine The ubiquitin ligase Nedd4 mediates oxidized low-density lipoprotein-induced downregulation of insulin-like growth factor-1 receptor Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1684 - H1689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bedel, A. Negre-Salvayre, S. Heeneman, M.-H. Grazide, J.-C. Thiers, R. Salvayre, and F. Maupas-Schwalm E-Cadherin/{beta}-Catenin/T-Cell Factor Pathway Is Involved in Smooth Muscle Cell Proliferation Elicited by Oxidized Low-Density Lipoprotein Circ. Res., September 26, 2008; 103(7): 694 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mallika, B. Goswami, and M. Rajappa Atherosclerosis Pathophysiology and the Role of Novel Risk Factors: A Clinicobiochemical Perspective Angiology, November 1, 2007; 58(5): 513 - 522. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Dentelli, A. Rosso, A. Zeoli, R. Gambino, L. Pegoraro, G. Pagano, R. Falcioni, and M. F. Brizzi Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and beta4 Integrin Expression J. Biol. Chem., September 7, 2007; 282(36): 26101 - 26110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. French, J. J. Upson, S. N. Keller, Y. Zhuang, J. K. Yun, and C. D. Smith Antitumor Activity of Sphingosine Kinase Inhibitors J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 596 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vindis, I. Escargueil-Blanc, M. Elbaz, B. Marcheix, M.-H. Grazide, K. Uchida, R. Salvayre, and A. Negre-Salvayre Desensitization of Platelet-Derived Growth Factor Receptor-{beta} by Oxidized Lipids in Vascular Cells and Atherosclerotic Lesions: Prevention by Aldehyde Scavengers Circ. Res., March 31, 2006; 98(6): 785 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Robbesyn, N. Auge, C. Vindis, A.-V. Cantero, R. Barbaras, A. Negre-Salvayre, and R. Salvayre High-Density Lipoproteins Prevent the Oxidized Low-Density Lipoprotein-Induced Endothelial Growth Factor Receptor Activation and Subsequent Matrix Metalloproteinase-2 Upregulation Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1206 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Suomalainen, V. Pentikainen, and L. Dunkel Sphingosine-1-Phosphate Inhibits Nuclear Factor {kappa}B Activation and Germ Cell Apoptosis in the Human Testis Independently of Its Receptors Am. J. Pathol., March 1, 2005; 166(3): 773 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vindis, M. Elbaz, I. Escargueil-Blanc, N. Auge, A. Heniquez, J.-C. Thiers, A. Negre-Salvayre, and R. Salvayre Two Distinct Calcium-Dependent Mitochondrial Pathways Are Involved in Oxidized LDL-Induced Apoptosis Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 639 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Maupas-Schwalm, C. Robinet, N. Auge, J.-C. Thiers, V. Garcia, J.-P. Cambus, R. Salvayre, and A. Negre-Salvayre Activation of the {beta}-Catenin/T-Cell-Specific Transcription Factor/Lymphoid Enhancer Factor-1 Pathway by Plasminogen Activators in ECV304 Carcinoma Cells Cancer Res., January 15, 2005; 65(2): 526 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Seasholtz and J. H. Brown RHO SIGNALING in Vascular Diseases Mol. Interv., December 1, 2004; 4(6): 348 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Le Stunff, A. Mikami, P. Giussani, J. P Hobson, P. S. Jolly, S. Milstien, and S. Spiegel Role of Sphingosine-1-phosphate Phosphatase 1 in Epidermal Growth Factor-induced Chemotaxis J. Biol. Chem., August 13, 2004; 279(33): 34290 - 34297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Auge, F. Maupas-Schwalm, M. Elbaz, J.-C. Thiers, A. Waysbort, S. Itohara, H.-W. Krell, R. Salvayre, and A. Negre-Salvayre Role for Matrix Metalloproteinase-2 in Oxidized Low-Density Lipoprotein-Induced Activation of the Sphingomyelin/Ceramide Pathway and Smooth Muscle Cell Proliferation Circulation, August 3, 2004; 110(5): 571 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]
|
|
|
|
|
|
H. Ohashi, H. Takagi, H. Oh, K. Suzuma, I. Suzuma, N. Miyamoto, A. Uemura, D. Watanabe, T. Murakami, T. Sugaya, et al. Phosphatidylinositol 3-Kinase/Akt Regulates Angiotensin II-Induced Inhibition of Apoptosis in Microvascular Endothelial Cells by Governing Survivin Expression and Suppression of Caspase-3 Activity Circ. Res., April 2, 2004; 94(6): 785 - 793. [Abstract] [Full Text] [PDF]
|
|