Oxidised-HDL3 induces the expression of PAI-1 in human endothelial cells. Role of p38MAPK activation and mRNA stabilization

Giuseppe Danilo Norata, Cristina Banfi, Angela Pirillo, Elena Tremoli, Anders Hamsten, Alberico L. Catapano, Per Eriksson

Research output: Contribution to journalArticlepeer-review

Abstract

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-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-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.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalBritish Journal of Haematology
Volume127
Issue number1
DOIs
Publication statusPublished - Oct 2004

Keywords

  • Atherosclerosis
  • Kinase
  • Lipoproteins
  • Oxidative modification
  • Thrombosis

ASJC Scopus subject areas

  • Hematology

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