title: OxLDL and macrophage survival: essential and oxygen-independent involvement of the Hif-pathway.
abstract: Atherosclerotic plaques are characterized by hypoxic even anoxic areas and by high concentrations of oxidized lipoproteins. Moreover, unstable plaques attract a high number of macrophages despite the proapoptotic background within these plaques. Recently, it was shown that these macrophages are positive for Hif-1α. This subunit is a part of hypoxia-inducible factor 1 (Hif-1), a key transcriptional factor under hypoxia. Till date, it is not understood whether the Hif-system (consisting of Hif-1, Hif-2 and Hif-3) is involved in protection of macrophages under these proatherogenic conditions. The present study delineates that oxLDL causes fundamental changes in the regulation of the Hif-system in primary human macrophages. First, both oxLDL and hypoxia mediate accumulation of Hif-1α protein. Second, treatment with a combination of oxLDL and hypoxia is acting in an additive manner on Hif-1α protein content. Third, oxLDL alone does not increase Hif-2α protein, but abolishes the hypoxic induction of Hif-2α completely. OxLDL treatment alone was not toxic for macrophages under neither normoxia nor hypoxia. But, inhibition of Hif-pathway by adenoviral expression of a dominant-negative mutant combined with oxLDL treatment independently of the oxygen tension leads to apoptosis, as determined by caspase-3 activation and induction of DNA fragmentation. Furthermore, this inhibition also mediates the opening of the mitochondrial permeability transition pore. In conclusion, the present data show that Hif-1α regulation is essential for survival of oxLDL-treated macrophages independent of the oxygen tension. Therefore, this newly characterized mechanism might also have an important influence for the vulnerability of atherosclerotic plaques.
authors.affiliation: Department of Internal Medicine and Cardiology, University of Technology Dresden, Fetscherstr. 74, 01307 Dresden, Germany. david.poitz@tu-dresden.de
authors.forename: David M
authors.initials: DM
authors.lastname: Poitz
authors.forename: Antje
authors.initials: A
authors.lastname: Augstein
authors.forename: Sönke
authors.initials: S
authors.lastname: Weinert
authors.forename: Rüdiger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmeisser
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D053148:Caspase 3 / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D010100:Oxygen / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C099252:oxidized low density lipoprotein