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Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells.
Am J Physiol Endocrinol Metab. 2008 Nov; 295(5):E1243-54.AJ

Abstract

Atherosclerotic cardiovascular disease is the number one cause of death for adults in Western society. Plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activators, has been implicated in both thrombogenesis and atherogenesis. Previous studies demonstrated that copper-oxidized low-density lipoprotein (C-oLDL) stimulated production of PAI-1 in vascular endothelial cells (EC). The present study examined the involvement of lectin-like oxidized LDL receptor-1 (LOX-1) and Ras/Raf-1/ERK1/2 pathway in the upregulation of PAI-1 in cultured EC induced by oxidized LDLs. The results demonstrated that C-oLDL or FeSO(4)-oxidized LDL (F-oLDL) increased the expression of PAI-1 or LOX-1 in human umbilical vein EC (HUVEC) or coronary artery EC (HCAEC). Treatment with C-oLDL significantly increased the levels of H-Ras mRNA, protein, and the translocation of H-Ras to membrane fraction in EC. LOX-1 blocking antibody, Ras farnesylation inhibitor (FTI-277), or small interference RNA against H-Ras significantly reduced C-oLDL or LDL-induced expression of H-Ras and PAI-1 in EC. Incubation with C-oLDL or F-oLDL increased the phosphorylation of Raf-1 and ERK1/2 in EC compared with LDL or vehicle. Treatment with Raf-1 inhibitor blocked Raf-1 phosphorylation and the elevation of PAI-1 mRNA level in EC induced by C-oLDL or LDL. Treatment with PD-98059, an ERK1/2 inhibitor, blocked C-oLDL or LDL-induced ERK1/2 phosphorylation or PAI-1 expression in EC. The results suggest that LOX-1, H-Ras, and Raf-1/ERK1/2 are implicated in PAI-1 expression induced by oxidized LDLs or LDL in cultured EC.

Authors+Show Affiliations

Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18796547

Citation

Sangle, Ganesh V., et al. "Transmembrane Signaling Pathway Mediates Oxidized Low-density Lipoprotein-induced Expression of Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells." American Journal of Physiology. Endocrinology and Metabolism, vol. 295, no. 5, 2008, pp. E1243-54.
Sangle GV, Zhao R, Shen GX. Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells. Am J Physiol Endocrinol Metab. 2008;295(5):E1243-54.
Sangle, G. V., Zhao, R., & Shen, G. X. (2008). Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells. American Journal of Physiology. Endocrinology and Metabolism, 295(5), E1243-54. https://doi.org/10.1152/ajpendo.90415.2008
Sangle GV, Zhao R, Shen GX. Transmembrane Signaling Pathway Mediates Oxidized Low-density Lipoprotein-induced Expression of Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells. Am J Physiol Endocrinol Metab. 2008;295(5):E1243-54. PubMed PMID: 18796547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells. AU - Sangle,Ganesh V, AU - Zhao,Ruozhi, AU - Shen,Garry X, Y1 - 2008/09/16/ PY - 2008/9/18/pubmed PY - 2009/1/13/medline PY - 2008/9/18/entrez SP - E1243 EP - 54 JF - American journal of physiology. Endocrinology and metabolism JO - Am J Physiol Endocrinol Metab VL - 295 IS - 5 N2 - Atherosclerotic cardiovascular disease is the number one cause of death for adults in Western society. Plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activators, has been implicated in both thrombogenesis and atherogenesis. Previous studies demonstrated that copper-oxidized low-density lipoprotein (C-oLDL) stimulated production of PAI-1 in vascular endothelial cells (EC). The present study examined the involvement of lectin-like oxidized LDL receptor-1 (LOX-1) and Ras/Raf-1/ERK1/2 pathway in the upregulation of PAI-1 in cultured EC induced by oxidized LDLs. The results demonstrated that C-oLDL or FeSO(4)-oxidized LDL (F-oLDL) increased the expression of PAI-1 or LOX-1 in human umbilical vein EC (HUVEC) or coronary artery EC (HCAEC). Treatment with C-oLDL significantly increased the levels of H-Ras mRNA, protein, and the translocation of H-Ras to membrane fraction in EC. LOX-1 blocking antibody, Ras farnesylation inhibitor (FTI-277), or small interference RNA against H-Ras significantly reduced C-oLDL or LDL-induced expression of H-Ras and PAI-1 in EC. Incubation with C-oLDL or F-oLDL increased the phosphorylation of Raf-1 and ERK1/2 in EC compared with LDL or vehicle. Treatment with Raf-1 inhibitor blocked Raf-1 phosphorylation and the elevation of PAI-1 mRNA level in EC induced by C-oLDL or LDL. Treatment with PD-98059, an ERK1/2 inhibitor, blocked C-oLDL or LDL-induced ERK1/2 phosphorylation or PAI-1 expression in EC. The results suggest that LOX-1, H-Ras, and Raf-1/ERK1/2 are implicated in PAI-1 expression induced by oxidized LDLs or LDL in cultured EC. SN - 0193-1849 UR - https://www.unboundmedicine.com/medline/citation/18796547/Transmembrane_signaling_pathway_mediates_oxidized_low_density_lipoprotein_induced_expression_of_plasminogen_activator_inhibitor_1_in_vascular_endothelial_cells_ L2 - https://journals.physiology.org/doi/10.1152/ajpendo.90415.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -