Published online before print October 24, 2002, doi: 10.1161/01.ATV.0000043453.21629.3B
© 2002 American Heart Association, Inc.
Vascular Biology |
Oxidized LDL-Induced Smooth Muscle Cell Proliferation Involves the EGF Receptor/PI-3 Kinase/Akt and the Sphingolipid Signaling Pathways
From INSERM U-466, Université Paul Sabatier, Toulouse, France.
Correspondence to A. Negre-Salvayre, Dr Pharm, PhD, INSERM U-466, Bat. L3, CHU. Rangueil, F-31403 Toulouse Cedex 4, France. 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
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