Palmitic and linoleic acids impair endothelial progenitor cells by inhibition of Akt/eNOS pathway

Background. Endothelial progenitor cells (EPCs) are involved in adult neovasculogenesis and maintenance of vascular integrity. Scarce data have been provided for the individual effect of elevated free fatty acids (FFAs) on EPCs. This study was designed to investigate the association between Akt/eNOS signal pathway changes and the proliferation/function of EPCs in the presence of palmitic and linoleic acids. Methods. After 14-day culture, EPCs were stimulated with different concentrations of palmitic and linoleic acids, with or without SNP, L-NAME, or LY294002. The proliferation and ability of adhesion, migration and tube structure formation of EPCs were observed and the level of phosphorylated Akt protein expression and eNOS protein expression were assayed. Results. Incubation with palmitic and linoleic acids at concentrations of 0.2 mu M or higher inhibited EPCs proliferation, significantly reduced migratory rate, reduced adhesion to fibronectin and impaired ability of EPCs to form tube structure in a dose-dependent manner. A simultaneous dose-dependent NO generation and Akt phosphorylation decrease as well as eNOS expression reduction at protein levels were also observed. However, all of the detrimental effects were attenuated by pretreating EPCs with SNP, NO donor. AKT and eNOS inhibitor, LY294002 and L-NAME, respectively, augmented palmitic and linoleic acids inhibitory effects on EPCs. Conclusions. These findings suggest that palmitic and linoleic acids downregulated AKT/cNOS signal pathway, which contributed to overall poor function and decrease proliferation of EPCs. These changes induced by palmitic and linoleic acids in signaling offer a novel explanation for the overall poor function of EPCs in diabetes mellitus. (C) 2008 IMSS. Published by Elsevier Inc.