Oxidised-HDL3 induces the expression of PAI-1 in human endothelial cells. Role of p38MAPK activation and mRNA stabilization.
Modified lipoproteins have been suggested to modulate endothelial expression of plasminogen activator inhibitor-1 (PAI-1). As oxidized high-density lipoprotein (Ox-HDL) has been found in atheromatous plaques and receptors for modified HDL are present on endothelial cells, we investigated the role of Ox-HDL3 on the expression of PAI-1. Ox-HDL3 but not native HDL3, increased PAI-1 mRNA expression in endothelial cells. Furthermore, PAI-1 antigen expression and activity increased in the supernatant of cells incubated with Ox-HDL3. The intracellular pathways involved in this effect were investigated. Ox-HDL3 activated both extracellular signal-regulated kinases (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK). Moreover, incubation with specific inhibitors of these kinases showed that p38MAPK was mainly involved in the Ox-HDL3-dependent PAI-1 induction. Transient transfection experiments suggested that none of the response elements in the proximal promoter (-804 to 17) were involved in Ox-HDL3-mediated PAI-1 expression. mRNA stability experiments showed that Ox-HDL3 increased the PAI-1 mRNA half-life. In summary, Ox-HDL3 induced PAI-1 mRNA expression and antigen release through a molecular mechanism involving MAPK activation and mRNA stabilization. Thus, oxidative modification converts HDL to a prothrombotic lipoprotein species.
Norata
Giuseppe D
GD
Department of Pharmacological Sciences, University of Milan, Milan, Italy. danilo.norata@unimi.it
Banfi
Cristina
C
Pirillo
Angela
A
Tremoli
Elena
E
Hamsten
Anders
A
Catapano
Alberico L
AL
Eriksson
Per
P
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D053440:Lipoproteins, HDL3; D010084:Oxidation-Reduction; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases