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

Medicine, Baylor College of Medicine, Houston, TX 77030

Corresponding Author: cchen{at}bcm.tmc.edu

Endothelial progenitor cells (EPCs), important for endothelial regeneration and vasculogenesis, is reduced by cigarette smoking. To elucidate the mechanisms, we examined the effects of electronegative low-density lipoprotein (LDL), circulating in chronic smokers, on EPC differentiation. Using ion-exchange chromatography, we purified smoker LDL into 5 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 LDL 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.

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