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Lox-1 receptor blockade abrogates oxLDL-induced oxidative DNA damage and prevents activation of the transcriptional repressor OCT-1 in human coronary arterial endothelium

: Thum, T.; Borlak, J.


The Journal of biological chemistry 283 (2008), Nr.28, S.19456-19464
ISSN: 0021-9258
ISSN: 1083-351X
Fraunhofer ITEM ()
atherosclerosis; oxidized lipoproteins; endothelial derived hyperpolarization factor; endothelial cell; oxidative stress; transcription factor; DNA damage

Activation of the lectin-like oxLDL receptor (LOX-1) promotes atherosclerosis. Oxidized LDL (OxLDL) increases production of reactive oxygen species (ROS) and leads to the development of endothelial dysfunction. The molecular causes for oxLDL to induce oxidative DNA damage and metabolic dysfunction remain uncertain. Treatment of cultured human coronary arterial endothelial cells (HCAEC) with oxLDL caused oxidative DNA damage as determined by a 3-fold increase in 8-OH-desoxyguanosine adduct formation and a 4-fold induction of the growth arrest and DNA damage inducible transcripts GADD45 and GADD153. Oxidative stress also resulted in activation of Oct-1, a transcriptional repressor of various vascular cytochrome P450 (CYP) monooxygenases. Activation of Oct-1 was protein kinase C (PKC)-mediated. Binding of Oct-1 to promoter sequences of CYP monooxygenases was increased upon treatment of HCAEC with oxLDL. This resulted in repressed production of endothelium derived hyperpolarisation factor 11,12-epoxyeicosatrieonic acid. Small interference RNA-mediated functional knockdown of Oct-1 prevented oxLDL-mediated silencing of CYP expression. Inhibition of LOX-1 attenuated oxLDL-mediated endothelial DNA damage, Oct-1/DNA binding and reversed impaired production of EDHF. Taken collectively, oxLDL induced oxidative DNA damage and activation of Oct-1 to result in metabolic dysfunction of coronary arterial endothelium.