当前位置： SCI文献检索 > CARDIOVASCULAR RESEARCH期刊下所有文献 > Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCalpha.

Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCalpha.

Abstract：

OBJECTIVE:Oxidized low-density lipoprotein (ox-LDL) increases superoxide anion (O(2)(-)) 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 Thr(495) was constitutively phosphorylated. ox-LDL, but not native LDL, enhanced the production of O(2)(-) 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 Thr(495). Protein kinase C (PKC) has been reported to phosphorylate this residue, and the increase in the phosphorylation of Thr(495) induced by phorbol 12-myristate 13-acetate was attenuated in cells pretreated with ox-LDL. Moreover, the phosphorylation and activity of PKCalpha 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 O(2)(-) than a T495D mutant did, indicating that the dephosphorylation of Thr(495) alone can increase O(2)(-) production by eNOS. However, although the dephosphorylation of Thr(495) 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 PKCalpha 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 O(2)(-).

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Fleming I,Mohamed A,Galle J,Turchanowa L,Brandes RP,Fisslthaler B,Busse R

doi

10.1016/j.cardiores.2004.11.003

subject

Has Abstract

pub_date

2005-03-01 00:00:00

pages

897-906

issue

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(04)00498-5

journal_volume

pub_type

杂志文章

在线工具

Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCalpha.