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Oxidised‐HDL 3 induces the expression of PAI‐1 in human endothelial cells. Role of p38MAPK activation and mRNA stabilization
Author(s) -
Norata Giuseppe D.,
Banfi Cristina,
Pirillo Angela,
Tremoli Elena,
Hamsten Anders,
Catapano Alberico L.,
Eriksson Per
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2004.05163.x
Subject(s) - mapk/erk pathway , kinase , messenger rna , plasminogen activator inhibitor 1 , plasminogen activator , transfection , protein kinase a , p38 mitogen activated protein kinases , lipoprotein , microbiology and biotechnology , activator (genetics) , extracellular , chemistry , receptor , signal transduction , biology , cholesterol , biochemistry , endocrinology , gene
Summary 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‐HDL 3 on the expression of PAI‐1. Ox‐HDL 3 but not native HDL 3 , increased PAI‐1 mRNA expression in endothelial cells. Furthermore, PAI‐1 antigen expression and activity increased in the supernatant of cells incubated with Ox‐HDL 3 . The intracellular pathways involved in this effect were investigated. Ox‐HDL 3 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‐HDL 3 ‐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‐HDL 3 ‐mediated PAI‐1 expression. mRNA stability experiments showed that Ox‐HDL 3 increased the PAI‐1 mRNA half‐life. In summary, Ox‐HDL 3 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.