VLDL activation of plasminogen activator inhibitor-1 (PAI-1) expression: Involvement of the VLDL receptor

Abstract

The potential role of the very low density lipo- protein (VLDL) receptor in mediating VLDL-induced plas- minogen activator inhibitor-1 (PAI-1) expression was stud- ied in vitro. Cultured endothelial cells incubated with VLDL showed an increased secretion of PAI-1. This response to VLDL could be completely prevented by the receptor-asso- ciated protein (RAP) and partially blocked by rabbit poly- clonal anti-VLDL receptor IgG. Furthermore, Chinese ham- ster ovary (CHO) control cells and cells overexpressing the VLDL receptor were transiently transfected with a PAI-1 promoter-reporter construct and incubated with VLDL. The PAI-1 promoter activity in response to VLDL was signif- icantly higher in the VLDL receptor overexpressing cells compared to the control cells. Addition of RAP completely blocked the VLDL-activated PAI-1 transcription. Electromo- bility shift assay was performed to investigate whether the enhanced PAI-1 promoter activity seen in the VLDL recep- tor overexpressing cells in response to VLDL involved in- duction of the previously described VLDL-inducible fac- tor(s) binding to the 2 675 to 2 653 region of the PAI-1 promoter. We found that the binding of the VLDL-inducible factor in VLDL receptor overexpressing cells was markedly enhanced by addition of VLDL as compared to control cells where no increased binding could be seen in response to VLDL. In summary, these results indicate that the VLDL receptor is a strong candidate for mediating VLDL effects on PAI-1 synthesis and secretion in cells expressing this re- ceptor.— Nilsson, L., M. Gafvels, L. Musakka, K. Ensler, D. K. Strickland, B. Angelin, A. Hamsten, and P. Eriksson. VLDL activation of plasminogen activator inhibitor-1 (PAI-1) ex- pression: involvement of the VLDL receptor. J. Lipid Res. 1999. 40: 913-919.