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Cardiovascular Research 2005 65(4):897-906; doi:10.1016/j.cardiores.2004.11.003
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Copyright © 2004, European Society of Cardiology

Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKC{alpha}

Ingrid Fleminga,*, Annisuddin Mohameda, Jan Galleb, Ljudmila Turchanowac, Ralf P. Brandesa, Beate Fisslthalera and Rudi Bussea

aInstitut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
bMedizinische Klinik, Schwerpunkt Nephrologie, Universität Wurzburg, Joseph-Schneider-Str. 2, 97080 Würzburg, Germany
cInstitut für Allgemeine Pharmakologie und Toxikologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

* Corresponding author. Tel.: +49 69 6301 6972; fax: +49 69 6301 7668. Email address: fleming{at}em.uni-frankfurt.de

Objective: Oxidized low-density lipoprotein (ox-LDL) increases superoxide anion (O2–) production by the endothelial nitric oxide (NO) synthase (eNOS). We assessed whether the uncoupling of eNOS was associated with alterations in eNOS phosphorylation and/or the assembly of the eNOS signaling complex.

Methods and results: In unstimulated human endothelial cells, eNOS Thr495 was constitutively phosphorylated. ox-LDL, but not native LDL, enhanced the production of O2– by endothelial cells, an effect that was partially sensitive to NOS inhibition. ox-LDL, but not native LDL, induced a time- and concentration-dependent decrease in the phosphorylation of eNOS on Thr495. Protein kinase C (PKC) has been reported to phosphorylate this residue, and the increase in the phosphorylation of Thr495 induced by phorbol 12-myristate 13-acetate was attenuated in cells pretreated with ox-LDL. Moreover, the phosphorylation and activity of PKC{alpha} was attenuated by ox-LDL and paralleled the changes in eNOS phosphorylation. ox-LDL also induced the dissociation of eNOS from the plasma and Golgi membranes. In COS-7 cells, a T495A eNOS mutant generated significantly more O2– than a T495D mutant did, indicating that the dephosphorylation of Thr495 alone can increase O2– production by eNOS. However, although the dephosphorylation of Thr495 in histamine-stimulated endothelial cells enhanced the binding of calmodulin to eNOS, calmodulin no longer bound to eNOS from ox-LDL-treated endothelial cells.

Conclusions: These results indicate that a decrease in the activity of PKC{alpha} in ox-LDL-treated endothelial cells is associated with the dephosphorylation of eNOS, dissociation of the eNOS signaling complex, and the enhanced production of eNOS-derived O2-.

KEYWORDS Endothelial function; Lipoproteins; Nitric oxide; Oxygen radicals; Protein kinase C

Time for primary review 21 days


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