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Journal of Lipid Research, Vol. 49, 33-47, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1

Daming Tang^*, Jonathan Lu^*, Jeffrey P. Walterscheid^*, Hsin-Hung Chen^*, David A. Engler, Tatsuya Sawamura, Po-Yuan Chang^**, Hazim J. Safi, Chao-Yuh Yang^* and Chu-Huang Chen^1,*

^* Department of Medicine, Baylor College of Medicine, Houston, TX
Department of Internal Medicine, University of Texas-Houston Medical School, Houston, TX
National Cardiovascular Research Institute, Suita, Osaka, Japan
^** Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Department of Cardiothoracic and Vascular Surgery, University of Texas-Houston Medical School, Houston, TX

Published, JLR Papers in Press, October 1, 2007.

¹ To whom correspondence should be addressed. e-mail: cchen{at}bcm.tmc.edu

Endothelial progenitor cells (EPCs), important for endothelial regeneration and vasculogenesis, are reduced by cigarette smoking. To elucidate the mechanisms, we examined the effects of electronegative LDL, circulating in chronic smokers, on EPC differentiation. Using ion-exchange chromatography, we purified smoker LDL into five subfractions, L1–L5. In matched, nonsmoking healthy subjects, L5, the most electronegative subfraction, was either absent or scanty. Sustained L5 treatment inhibited CD31 and KDR expression and EPC differentiation, whereas L1–L4 had no effect. L5 also inhibited telomerase activity to accelerate EPC senescence in correlation with reduced Akt phosphorylation. Transfection of day 3 EPCs with dominant negative Akt constructs inhibited CD31 and KDR expression, stalled EPC differentiation, and promoted early senescence. In contrast, transfection with constitutively active Akt rendered the EPCs resistant to L5, allowing normal maturation. L5 upregulated the lectin-like oxidized low density lipoprotein receptor 1 (LOX-1), and pretreatment of EPCs with TS20, a LOX-1-neutralizing antibody, blocked internalization of L5 by EPCs and prevented L5-mediated inhibition of EPC differentiation. Mixing L5 with L1 to physiological L5/L1 ratios did not attenuate L5's effects. These findings suggest that cigarette smoking is associated with the formation of L5, which inhibits EPC differentiation by impairing Akt phosphorylation via the LOX-1 receptor.

Supplementary key words electronegative low density lipoprotein • L5 • lectin-like oxidized low density lipoprotein receptor 1 • signal transduction

Abbreviations: AcLDL, acetylated low density lipoprotein; Akt-CA, plncx-HA-myr-Akt (constitutively active Akt); Akt-DN, plncx-HA-myr-Akt179M (dominant negative Akt); DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine; EC, endothelial cell; EGF, epidermal growth factor; EPC, endothelial progenitor cell; LOX-1, lectin-like oxidized low density lipoprotein receptor 1; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-tetrazolium; OxLDL, experimentally oxidized low density lipoprotein; SA-β-gal, senescence-associated β-galactosidase; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor

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