© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
PKC/Raf/MEK/ERK signaling pathway modulates native-LDL-induced E2F-1 gene expression and endothelial cell proliferation
aDepartment of Biomedical Sciences, Division of Biochemistry, Laboratory of Cardiovascular Research, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
bDivision of Cell Biology, National Institute of Biostructures and Biosystems, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
cInstitute of Clinical Biochemistry, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
gpintus{at}uniss.it
gionfry_p{at}yahoo.it
* Corresponding author. Department of Biomedical Sciences, Division of Biochemistry, Laboratory of Cardiovascular Research, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy. Tel.: +39-079-228-121; fax: +39-079-228-120.
Background and objectives: The interactions of low-density lipoprotein (LDL) with the endothelium are thought to play a major role in the development of atherosclerosis. Due to this reason, the molecular sequelae of events resulting from native LDL (N-LDL) interaction with human endothelial cells (HECs) are largely under investigation. Methods and results: Here, we report that the exposure of serum-free HECs to different concentrations of N-LDL-cholesterol (LDL-chol) elicited a time- and dose-dependent induction of DNA synthesis. The exposure of serum-free HECs to N-LDL was able to elicit a time- and dose-dependent increase of protein kinase C (PKC) activity that, along with the activation of the Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, leads to an increase in E2F-1 gene expression. In addition, the treatment of HECs with N-LDL was also able to induce both E2F-1 gene transcription and protein expression. These N-LDL-aroused responses were dramatically counteracted by PKC inhibition or down regulation. Similarly to what observed for Raf/MEK/ERK activation and E2F-1 gene expression, the inhibition of PKC as well as its down regulation, significantly lowered the DNA synthesis induced by N-LDL in serum-free HECs. Conclusions: These results suggest that the activation of PKC/Raf/MEK/ERK-mediated events controlling E2F-1 gene expression by N-LDL may represent an important mechanism in the regulation of HECs proliferation during normal and pathological processes.
KEYWORDS Endothelial function; Gene expression; Lipoproteins; Protein kinases; Signal transduction
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